Quinazoline derivatives and their use as DNA methyltransferase inhibitors

ABSTRACT

The present invention relates to compounds of the following formula (I): and pharmaceutically acceptable salts and solvates thereof, their methods of preparation, their use as a drug, notably in the treatment of cancer, and pharmaceutical compositions containing such compounds.

The present invention relates to quinazoline derivatives useful as DNA methyltransferase (DNMT) inhibitors, notably in the treatment of cancer.

Gene expression is known to be controlled by epigenetic modifications. Methylation of deoxycytidines (dC) in the DNA was shown to play a key role in epigenetic regulation in mammals (Berger et al. Genes Dev. 2009, 23, 781; Kelly et al. Biotechnol. 2010, 28, 1069). It is the most stable epigenetic mark and occurs at CpG sites, which are regrouped in island and essentially located in promoters, repeated sequences and CpG island shores (Gros et al. Biochimie 2012, 94, 2280). Hypermethylation of promoters' CpG islands induces gene silencing while hypomethylation induces gene expression (Sharma et al. Carcinogenesis 2010, 31, 27; Esteller N. Engl. J. Med. 2008, 358, 1148).

The enzymes responsible for DNA methylation are DNA methyltransferases (DNMTs). Two families of catalytically-active DNMTs have been identified: DNMT1, responsible for DNA methylation maintenance during replication, and DNMT3A and 3B, responsible for de novo DNA methylation. DNMTs add a methyl group on the carbon-5 position of the deoxycytosine at the CpG site in the DNA by using S-adenosyl-L-methionine (AdoMet) as methyl donor (Jurkowska et al. ChemBioChem 2011, 12, 206).

Alteration of DNA methylation patterns lead to various diseases such as cancer (Baylin and Jones Nat. Rev. Cancer 2011, 11, 726). Cancerous cells often present aberrant DNA methylation, in particular a specific hypermethylation of tumour suppressor genes is observed. Restoring their expression by specific inhibition of DNA methylation represents an attractive therapeutic strategy (Kelly et al. Biotechnol. 2010, 28, 1069; Fahy et al. Expert Opin. Ther. Pat. 2012, 22, 1427).

DNMT inhibitors can be divided into two families: nucleoside analogues and non-nucleosides. The first are the most active ones. Two of them were FDA approved: 5-azacytidine (Vidaza®) and 5-azadeoxycytidine (Dacogene®) (Gros et al. Biochimie 2012, 94, 2280). Despite their high efficiency, their poor bioavailability, their instability in physiologic media and their little selectivity restrict their use (Fahy et al. Expert Opin. Ther. Pat. 2012, 22, 1427). Non-nucleoside analogues present various structures and mechanisms of action. Many of them were shown to target the catalytic site but suffer from high toxicity, lack of specificity and weak activity.

There exists thus a need for novel DNMT inhibitors.

The inventors of the present invention have thus discovered that quinazoline derivatives can be used as DNA methyltransferase (DNMT) inhibitors.

The present invention concerns thus a compound of the following formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   represents a single bond or a double bond on the condition that         the two bonds         do not represent a double bond at the same time,     -   n1 and n2 represent, independently of each other, an integer         comprised between 0 and 8, notably between 1 and 8,     -   Q represents an optionally substituted aryl or an optionally         substituted heterocycle,     -   W represents a bond, NR₀, a piperidinediyl, a piperazinediyl or         a pyrrolidinediyl,     -   X₁ represents O or NR₁,     -   X₂ represents O or NR₂,     -   X₃ represents:         -   N when             X₃ represents a double bond ═X₃, and         -   NR₃ when             X₃ represents a single bond —X₃,     -   X₄ represents:         -   O or NR₄ when             X₄ represents a double bond ═X₄, and         -   —OR₄ or NR₄R₅ when             X₄ represents a single bond —X₄,     -   —R₀ represents H; CHO; CO₂—((C₁-C₆)alkyl); or a (C₁-C₆)alkyl         optionally substituted with CHO, CO₂H or CO₂—((C₁-C₆)alkyl),     -   R₁ and R₂ represent, independently of each other, H or a         (C₁-C₆)alkyl,     -   R₃ and R₄ represent, independently of each other, H,         (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or         —((C₁-C₆)alkyl)-X₅-heterocycle,     -   with X₅ representing a bond, O or NR₆ and each aryl or         heterocycle moiety being optionally substituted, and     -   R₅ and R₆ represent, independently of each other, H or a         (C₁-C₆)alkyl.

For the purpose of the invention, the term “pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.

The term “pharmaceutically acceptable salt or solvate” is intended to mean, in the framework of the present invention, a salt or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.

The pharmaceutically acceptable salts comprise:

(1) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl-L-tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and

(2) base addition salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. As an example, mention may be made of solvates due to the presence of water (these solvates are also called hydrates) or ethanol.

The term “(C₁-C₆)alkyl”, as used in the present invention, refers to a straight or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

The term “(C₂-C₆)alkenyl”, as used in the present invention, refers to a straight or branched unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms and comprising at least one double bond, notably one double bond, including, but not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like. It can be in particular an allyl group.

The term “aryl”, as used in the present invention, refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more, notably 1 or 2, fused rings, such as, for example, a phenyl or naphtyl group. Advantageously, it will be a phenyl group.

The term “aryl-(C₁-C₆)alkyl”, as used in the present invention, refers to an aryl group as defined above bound to the molecule via a (C₁-C₆)alkyl group as defined above. In particular, the aryl-(C₁-C₆)alkyl group is a benzyl group.

The term “(C₁-C₆)alkyl-aryl”, as used in the present invention, refers to a (C₁-C₆)alkyl group as defined above bound to the molecule via an aryl group as defined above. In particular, it can be a tolyl group (-PhCH₃).

The term “heterocycle” as used in the present invention refers to a saturated, unsaturated or aromatic hydrocarbon monocycle or polycycle (comprising fused, bridged or spiro rings), such as a bicycle, in which one or more, advantageously 1 to 4, and more advantageously 1 or 2, carbon atoms have each been replaced with a heteroatom selected from nitrogen, oxygen and sulphur atoms, and notably being a nitrogen atom. Advantageously, the heterocycle comprises 5 to 15, notably 5 to 10 atoms in the ring(s). The ring(s) of the heterocycle has/have advantageously 5 or 6 members.

According to a particular embodiment, the heterocycle is a saturated, unsaturated or aromatic hydrocarbon monocycle or bicycle (comprising fused, bridged or spiro rings, notably fused rings), each cycle having 5 or 6 members and 1 to 4, notably 1 or 2, carbon atoms having each been replaced with a nitrogen or oxygen atom, notably a nitrogen atom.

A heterocycle can be notably thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazoles (1,2,3-triazole and 1,2,4-triazole), benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, piperidine, piperazine, triazinane, morpholine, pyrrolidine, dihydropyridines, dihydropyrimidines (notably 1,2-dihydropyrimidine), dihydropyridazines, dihydropyrazines, dihydrotriazines, tetrahydropyridines, tetrahydropyrimidines, tetrahydropyridazines, tetrahydropyrazines, tetrahydrotriazines, etc.

The term “heterocycle-(C₁-C₆)alkyl”, as used in the present invention, refers to a heterocycle group as defined above bound to the molecule via a (C₁-C₆)alkyl group as defined above.

The term “heteroaryl” as used in the present invention refers to an aromatic heterocycle as defined above.

According to a particular embodiment, the heteroaryl is an aromatic hydrocarbon monocycle or bicycle (i.e. comprising fused rings), each cycle having 5 or 6 members, notably 6 members, and 1 to 4, notably 1 or 2, carbon atoms having each been replaced with a nitrogen or oxygen atom, notably a nitrogen atom.

A heteroaryl can be notably thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazoles (1,2,3-triazole and 1,2,4-triazole), benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, etc.

The term “heteroaryl-(C₁-C₆)alkyl”, as used in the present invention, refers to a heteroaryl group as defined above bound to the molecule via a (C₁-C₆)alkyl group as defined above.

The term “piperidinediyl”, as used in the present invention, refers to a divalent piperidine moiety. It can be in particular

The term “piperazinediyl”, as used in the present invention, refers to a divalent piperazine moiety. It can be in particular

The term “pyrrolidinediyl”, as used in the present invention, refers to a divalent pyrrolidine moiety. It can be in particular

An “optionally substituted” radical, as used in the present invention, refers to a radical optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; S(O)R₅₀; S(O)₂R₅₁; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅, and S(O)₂NR₅₆R₅₇; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, NR₃₉C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁,

with R₁₁ to R₄₀ and R₅₀ to R₆₁ representing, independently of one another, H or (C₁-C₆)alkyl.

An “optionally substituted” radical can be in particular a radical optionally substituted with one or several groups selected from halogen; oxo (═O); OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; and aryl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀, with R₁₁ to R₄₀ as defined previously.

The term “halogen”, as used in the present invention, refers to a fluorine, bromine, chlorine or iodine atom.

According to a particular embodiment of the present invention, the compound of the present invention is a compound of the following formula (I-1):

or a pharmaceutically acceptable salt or solvate thereof.

The formula (I) of the present invention comprises two bonds

. According to a particular embodiment, one of them is a single bond and the other is a double bond. Thus the compound of the present invention can correspond to a compound of the following formulas (Ia) and (Ib), preferably of the following formulas (I-1a) and (I-1b):

preferably

or a pharmaceutically acceptable salt or solvate thereof.

In particular, n1 can represent 0, 1, 2, 3 or 4, notably 1, 2, 3, or 4.

In particular, n2 can represent 0, 1, 2, 3 or 4, notably 1, 2, 3, or 4, such as 2 or 3.

X₁ represents advantageously NH or O, in particular NH.

X₂ represents advantageously NH or O, in particular O.

According to a particular embodiment, X₁ represents NR₁ and X₂ represents O, notably X₁ represents NH and X₂ represents O.

According to a first embodiment, W represents a bond, NR₀, a piperidinediyl or a piperazinediyl. Advantageously, W represents NR₀, a piperidinediyl or a piperazinediyl, notably NR₀ or a piperidinediyl.

According to a second embodiment, W represents a bond, NR₀, a piperidinediyl, a piperazinediyl or a pyrrolidinediyl. Advantageously, W represents NR₀, a piperidinediyl, a piperazinediyl or a pyrrolidinediyl, notably NR₀, a piperidinediyl or a pyrrolidinediyl.

In these two embodiments, the piperidinediyl group can be

and in particular is

the nitrogen atom being linked to (CH₂)_(n1). The piperazinediyl group is in particular

The pyrrolidinediyl group can be

and in particular is

the nitrogen atom being linked to (CH₂)_(n1).

R₀ represents notably H; CHO; or a (C₁-C₆)alkyl optionally substituted with CO₂H or CO₂—((C₁-C₆)alkyl) (e.g. CO₂Me). According to a first particular embodiment, R₀ represents H. According to a second particular embodiment, R₀ represents CHO or CO₂—((C₁-C₆)alkyl), such as CHO. According to a third particular embodiment, R₀ represents a (C₁-C₆)alkyl optionally substituted with CHO, CO₂H or CO₂—((C₁-C₆)alkyl), notably with CO₂H or CO₂—((C₁-C₆)alkyl) (e.g. CO₂Me).

Q represents notably an aryl or heterocycle, notably a heterocycle, optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; S(O)R₅₀; S(O)₂R₅₁; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅, and S(O)₂NR₅₆R₅₇; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, NR₃₉C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁, with R₁₁ to R₄₀ and R₅₀ to R₆₁ representing, independently of one another, H or (C₁-C₆)alkyl.

Q represents notably an aryl or heterocycle, notably a heterocycle, optionally substituted with one or several groups selected from halogen; oxo (═O); OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; and aryl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀,

with R₁₁ to R₄₀ representing, independently of one another, H or (C₁-C₆)alkyl.

Q represents in particular an aryl or heterocycle, notably a heterocycle, optionally substituted with one or several groups selected from halogen; oxo (═O); (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; and aryl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀.

Q can also represent an aryl or heterocycle, notably a heterocycle, optionally substituted with one or several groups selected from halogen; oxo (═O); OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; and (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀.

Q can represent in particular an aryl or heterocycle, notably a heterocycle, optionally substituted with one or several groups selected from halogen; oxo (═O); OR₁₁; NR₁₂R₁₃; and (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁ and NR₂₂R₂₃.

Q represents particularly an aryl or heterocycle, notably a heterocycle, optionally substituted with one or several groups selected from halogen; oxo (═O); and (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁ and NR₂₂R₂₃.

In the definitions of Q above, the aryl is preferably a phenyl or a naphtyl, in particular a phenyl.

In the definitions of Q above, the heterocycle is notably a saturated, unsaturated or aromatic hydrocarbon monocycle or bicycle (comprising fused, bridged or spiro rings, notably fused rings), each cycle having 5 or 6 members and 1 to 4, notably 1 or 2, carbon atoms having each been replaced with a nitrogen or oxygen atom, notably a nitrogen atom. The heterocycle can be notably chosen among pyrrole, imidazole, pyrazole, triazoles, indole, benzimidazole, indazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, piperidine, piperazine, triazinane, pyrrolidine, dihydropyridines, dihydropyrimidines (notably 1,2-dihydropyrimidine), dihydropyridazines, dihydropyrazines, dihydrotriazines, tetrahydropyridines, tetrahydropyrimidines, tetrahydropyridazines, tetrahydropyrazines and tetrahydrotriazines. In particular, the heterocycle can be chosen among pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, quinoxaline, quinazoline, piperidine, piperazine, dihydropyridines, dihydropyrimidines (notably 1,2-dihydropyrimidine), dihydropyridazines, dihydropyrazines, tetrahydropyridines, tetrahydropyrimidines, tetrahydropyridazines and tetrahydropyrazines. More particularly, the heterocycle can be chosen among quinoline, quinazoline, pyridine, pyrimidine and dihydropyrimidines (notably 1,2-dihydropyrimidine). Notably, the heterocycle can be chosen among quinoline, pyridine and dihydropyrimidines (notably 1,2-dihydropyrimidine).

In the definitions of Q above, the heterocycle is preferably an heteroaryl, such as an aromatic hydrocarbon monocycle or bicycle (i.e. comprising fused rings), each cycle having 5 or 6 members, notably 6 members, and 1 to 4, notably 1 or 2, carbon atoms having each been replaced with a nitrogen or oxygen atom, notably a nitrogen atom. Preferably, the heretoaryl is an aromatic hydrocarbon monocycle or bicycle (i.e. comprising fused rings), each cycle having 6 members, and 1 or 2 carbon atoms having each been replaced with a heteroatom chosen among nitrogen and oxygen atoms, at least one heteroatom being a nitrogen atom and preferably all the heteroatoms being a nitrogen atom when two heteroatoms are present. The heteroaryl can be notably chosen among thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazoles (1,2,3-triazole and 1,2,4-triazole), benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline and quinazoline. In particular, the heteroaryl can be chosen among pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinoline, quinoxaline, and quinazoline. Notably, the heteroaryl can be chosen among quinoline, quinazoline, pyridine and pyrimidine. In particular, it is quinoline or pyridine.

According to a preferred embodiment, Q represents a cycle of the following formula:

wherein:

-   -   X₁₁ represents N or CR₄₁,     -   X₁₂ represents N or CR₄₂,     -   X₁₃ represents N or C—NR_(43a)R_(43b),     -   X₁₄ represents N or CR₄₄,     -   X₁₅ represents N or CR₄₅,     -   R_(43a) and R_(43b) each represent, independently of each other,         H or (C₁-C₆)alkyl, and in particular H,     -   R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each         other, hydrogen; halogen; NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅;         OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; S(O)R₅₀; S(O)₂R₅₁;         S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or         several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄,         CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅,         and S(O)₂NR₅₆R₅₇; or aryl or aryl-(C₁-C₆)alkyl optionally         substituted with one or several groups selected from halogen,         OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈,         NR₃₉C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁, or         in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of         the following formula:

wherein:

-   -   X₁₆ represents N or CR₄₆,     -   X₁₇ represents N or CR₄₇,     -   X₁₈ represents N or CR₄₈,     -   X₁₉ represents N or CR₄₉, and     -   R₄₆, R₄₇, R₄₈ and R₄₉ each represent, independently of one         another, hydrogen; halogen; NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅;         OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; S(O)R₅₀; S(O)₂R₅₁;         S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or         several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄,         CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅,         and S(O)₂NR₅₆R₅₇; or aryl or aryl-(C₁-C₆)alkyl optionally         substituted with one or several groups selected from halogen,         OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈,         NR₃₉C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁,         on the proviso that no more than three, notably two, and         preferably one, of X₁₁, X₁₂, X₁₄, X₁₅, X₁₆, X₁₇, X₁₈ and X₁₉         represent N.

In particular, none of X₁₁, X₁₂, X₁₄, X₁₅, X₁₆, X₁₇, X₁₈ and X₁₉ represents N.

Advantageously, R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each other, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; or aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀, or in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of the following formula:

with R₄₆, R₄₇, R₄₈ and R₄₉ each representing, independently of one another, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; or aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀.

In particular, R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each other, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; or (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀, or

in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of the following formula:

with R₄₆, R₄₇, R₄₈ and R₄₉ each representing, independently of one another, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; or (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀.

Notably, R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each other, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; or (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, and NR₂₂R₂₃, or

in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of the following formula:

with R₄₆, R₄₇, R₄₈ and R₄₉ each representing, independently of one another, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; or (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, and NR₂₂R₂₃.

In particular, R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each other, hydrogen; halogen; OR₁₁; or NR₁₂R₁₃; and notably hydrogen, or in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of the following formula:

with R₄₆, R₄₇, R₄₈ and R₄₉ each representing, independently of one another, hydrogen; halogen; OR₁₁; or NR₁₂R₁₃.

According to a most preferred embodiment, Q represents one of the following cycles:

with R_(43a) and R_(43b) as defined above and in particular representing H, and with R₄₁, R₄₂ and R₄₄ to R₄₉ as defined above, and in particular with R₄₁, R₄₂ and R₄₄ to R₄₉ each representing, independently of one another, hydrogen; halogen; OR₁₁; or NR₁₂R₁₃.

In particular, Q represents one of the following cycles:

with R_(43a) and R_(43b) as defined above and in particular representing H, and with R₄₆ to R₄₉ each representing, independently of one another, hydrogen; halogen; OR₁₁; or NR₁₂R₁₃.

-   -   Q can be for example one of the following cycles:

According to a particular embodiment, X₃ represents:

-   -   N when         X₃ represents a double bond ═X₃, and     -   NR₃ when         X₃ represents a single bond —X₃,

According to another particular embodiment, X₄ represents:

-   -   O when         X₄ represents a double bond ═X₄, and     -   NR₄R₅ when         X₄ represents a single bond —X₄,

The compound of the present invention can correspond in particular to a compound of the following formulas (Ic) and (Id), preferably of the following formulas (I-1c) and (I-1d):

preferably

or a pharmaceutically acceptable salt or solvate thereof.

More particularly, R₃ and R₄ will represent, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle, each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; S(O)R₅₀; S(O)₂R₅₁; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅, and S(O)₂NR₅₆R₅₇; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, NR₃₀C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁,

with R₁₁ to R₄₀ and R₅₀ to R₆₁ representing, independently of one another, H or (C₁-C₆)alkyl.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; S(O)R₅₀; S(O)₂R₅₁; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, S(O)R₅₄, S(O)₂R₅₅, and S(O)₂NR₅₆R₅₇; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; S(O)R₅₀; S(O)₂R₅₁; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, and NR₂₂R₂₃; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, and NR₃₂R₃₃.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, and S(O)₂NR₅₆R₅₇; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, and S(O)₂NR₆₀R₆₁.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, and NR₂₂R₂₃; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, and NR₃₂R₃₃.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl; aryl; and aryl-(C₁-C₆)alkyl.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; and aryl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; OR₁₁; NR₁₂R₁₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁ and NR₂₂R₂₃; and aryl optionally substituted with one or several groups selected from halogen, OR₃₁ and NR₃₂R₃₃.

R₃ and R₄ represent notably, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, aryl-(C₁-C₆)alkyl, heterocycle-(C₁-C₆)alkyl, —((C₁-C₆)alkyl)-NH-aryl or —((C₁-C₆)alkyl)-NH-heterocycle,

each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; OR₁₁; NR₁₂R₁₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁ and NR₂₂R₂₃; and aryl optionally substituted with one or several groups selected from halogen, OR₃₁ and NR₃₂R₃₃.

In the definitions of R₃ and R₄ above, the aryl preferably is a phenyl or a naphtyl, in particular a phenyl.

In the definitions of R₃ and R₄ above, the heterocycle is notably a saturated, unsaturated or aromatic (notably aromatic) hydrocarbon monocycle or bicycle (comprising fused, bridged or spiro rings, notably fused rings), each cycle having 5 or 6 members and 1 to 4, notably 1 or 2, carbon atoms having each been replaced with a nitrogen or oxygen atom, notably a nitrogen atom. The heterocycle can be a heteroaryl. The heterocycle can be notably chosen among pyrrole, imidazole, pyrazole, triazoles, indole, benzimidazole, indazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, piperidine, piperazine, triazinane, pyrrolidine, dihydropyridines, dihydropyrimidines (notably 1,2-dihydropyrimidine), dihydropyridazines, dihydropyrazines, dihydrotriazines, tetrahydropyridines, tetrahydropyrimidines, tetrahydropyridazines, tetrahydropyrazines and tetrahydrotriazines. According to a first embodiment, the heterocycle is chosen among pyrrole, imidazole, pyrazole, triazoles, indole, benzimidazole, indazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline and quinazoline; notably chosen among pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline and quinazoline. According to a second embodiment, the heterocycle is chosen among piperidine, piperazine, triazinane or pyrrolidine; and in particular is piperidine.

In the definitions of R₃ and R₄ above, X₅ represents in particular a bond or NR₆, notably a bond or NH.

According to a preferred embodiment, R₅ represents H.

According to a particular embodiment, the compounds according to the present invention are compounds of formula (I-1c) or (I-id), or a pharmaceutically acceptable salt or solvate thereof,

wherein:

-   -   n1 and n2 represent, independently of each other, 1, 2, 3 or 4,     -   Q represents an aryl or heteroaryl optionally substituted with         one or several groups selected from halogen; oxo (═O); OR₁₁;         NR₁₂R₁₃; and (C₁-C₆)alkyl optionally substituted with one or         several groups selected from halogen, OR₂₁ and NR₂₂R₂₃.     -   W represents a bond, NR₀,

the nitrogen atom being linked to (CH₂)_(n1); notably NR₀,

the nitrogen atom being linked to (CH₂)_(n1),

-   -   X₁ represents NH,     -   X₂ represents O,     -   R₀ represents H; CHO; or a (C₁-C₆)alkyl optionally substituted         with CO₂H or CO₂—((C₁-C₆)alkyl),     -   R₃ and R₄ represent, independently of each other, H,         (C₁-C₆)alkyl, aryl heterocycle, aryl-(C₁-C₆)alkyl,         heterocycle-(C₁-C₆)alkyl, —((C₁-C₆)alkyl)-NH-aryl or         —((C₁-C₆)alkyl)-NH-heterocycle, notably, H, (C₁-C₆)alkyl,         heterocycle, aryl-(C₁-C₆)alkyl, or —((C₁-C₆)alkyl)-NH-aryl,     -   each aryl or heterocycle moiety being optionally substituted         with one or several groups selected from halogen; oxo (═O); NO₂;         OR₁₁; NR₁₂R₁₃; C(O)R₁₄; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally         substituted with one or several groups selected from halogen,         OR₂₁, and NR₂₂R₂₃; and aryl or aryl-(C₁-C₆)alkyl optionally         substituted with one or several groups selected from halogen,         OR₃₁, and NR₃₂R₃₃, and     -   R₅ represents H,         wherein:     -   the aryl is phenyl,     -   the heterocycle is a saturated hydrocarbon monocycle or bicycle         (comprising fused, bridged or spiro rings, notably fused rings),         each cycle having 5 or 6 members and 1 to 4, notably 1 or 2,         carbon atoms having each been replaced with a nitrogen or oxygen         atom, notably a nitrogen atom; such as piperidine, piperazine,         triazinane or pyrrolidine; and in particular piperidine, and     -   the heteroaryl is an aromatic hydrocarbon monocycle or bicycle         (comprising fused rings), each cycle having 5 or 6 members and 1         to 4, notably 1 or 2, carbon atoms having each been replaced         with a nitrogen or oxygen atom, notably a nitrogen atom; such as         pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline,         isoquinoline, quinoxaline or quinazoline; in particular pyridine         or quinoline.

According to another particular embodiment, the compounds according to the present invention are compounds of formula (I-1c) or (I-1d), or a pharmaceutically acceptable salt or solvate thereof,

wherein:

-   -   n1 and n2 represent, independently of each other, 1, 2, 3 or 4,     -   Q represents an aryl or heterocycle, notably a heterocycle,         optionally substituted with one or several groups selected from         halogen; oxo (═O); and (C₁-C₆)alkyl optionally substituted with         one or several groups selected from halogen, OR₂₁ and NR₂₂R₂₃.     -   W represents a bond, NR₀ or

the nitrogen atom being linked to (CH₂)_(n1); notably NR₀ or

the nitrogen atom being linked to (CH₂)_(n1),

-   -   X₁ represents NH,     -   X₂ represents O,     -   R₀ represents H; CHO; or a (C₁-C₆)alkyl optionally substituted         with CO₂H or CO₂—((C₁-C₆)alkyl),     -   R₃ and R₄ represent, independently of each other, H,         (C₁-C₆)alkyl, aryl, heteroaryl, aryl-(C₁-C₆)alkyl,         heteroaryl-(C₁-C₆)alkyl, —((C₁-C₆)alkyl)-NH-aryl or         —((C₁-C₆)alkyl)-NH-heteroaryl,     -   each aryl or heteroaryl moiety being optionally substituted with         one or several groups selected from halogen; OR₁₁; NR₁₂R₁₃;         (C₁-C₆)alkyl optionally substituted with one or several groups         selected from halogen, OR₂₁ and NR₂₂R₂₃; and aryl optionally         substituted with one or several groups selected from halogen,         OR₃₁ and NR₃₂R₃₃, and     -   R₅ represents H,         wherein:     -   the aryl is phenyl,     -   the heterocycle is a saturated, unsaturated or aromatic         hydrocarbon monocycle or bicycle (comprising fused, bridged or         spiro rings, notably fused rings), each cycle having 5 or 6         members and 1 to 4, notably 1 or 2, carbon atoms having each         been replaced with a nitrogen or oxygen atom, notably a nitrogen         atom; such as pyridine, pyrimidine, pyridazine, pyrazine,         quinoline, isoquinoline, quinoxaline, quinazoline, piperidine,         piperazine, dihydropyridines, dihydropyrimidines,         dihydropyridazines, dihydropyrazines, tetrahydropyridines,         tetrahydropyrimidines, tetrahydropyridazines or         tetrahydropyrazines; in particular quinoline, pyridine or         dihydropyrimidines (notably 1,2-dihydropyrimidine), and     -   the heteroaryl is an aromatic hydrocarbon monocycle or bicycle         (comprising fused rings), each cycle having 5 or 6 members and 1         to 4, notably 1 or 2, carbon atoms having each been replaced         with a nitrogen or oxygen atom, notably a nitrogen atom; such as         pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline,         isoquinoline, quinoxaline or quinazoline; in particular         quinoline or pyrimidine.

The compounds of the present invention may be selected from compounds A to U described in the experimental part below and the pharmaceutically acceptable salts and solvates thereof.

The compounds of the present invention can also be selected from compounds AA to AS described in the experimental part below and the pharmaceutically acceptable salts and solvates thereof.

The present invention relates also to a compound of formula (I) such as defined above, for use as a drug, notably intended for the treatment of cancer.

The present invention also relates to the use of a compound of formula (I) such as defined above, for the manufacture of a drug, notably intended for the treatment of cancer.

The present invention also relates to a method for the treatment of cancer comprising the administration to a person in need thereof of an effective dose of a compound of formula (I) such as defined above.

The cancer may be more particularly in this case colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, glioblastoma, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, leukemia (acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia), melanoma, diffuse B-cell lymphoma or anaplastic large-cell lymphoma.

The present invention relates also to a compound of formula (I) such as defined above, for use as a DNA methylation inhibitor, in particular as a DNMT inhibitor.

According to the invention, the expression “DNA methylation inhibitor” and “DNMT inhibitor” refers to molecules that are able to reduce or inhibit the DNA methylation and the DNA methyltransferase activity respectively. Preferentially, the use of a DNMT inhibitor according to the invention makes it possible to suppress the activity of said DNMT.

The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) such as defined above, and at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions according to the invention may be formulated notably for oral administration or for injection, wherein said compositions are intended for mammals, including humans.

The pharmaceutical composition can be administered orally by means of tablets and gelatin capsules.

When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. The tablets may be coated with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and they continuously release a predetermined amount of active principle.

A preparation in gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.

For administration by injection, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents are used.

The active ingredient may be administered in unit dosage forms of administration, in mixture with standard pharmaceutical carriers, to animals or to humans. The compounds of the invention as active ingredients may be used in doses ranging between 0.01 mg and 1000 mg per day, given in a single dose once per day or administered in several doses throughout the day, for example twice a day in equal doses. The dose administered per day advantageously is between 5 mg and 500 mg, even more advantageously between 10 mg and 200 mg. It may be necessary to use doses outside these ranges as determined by the person skilled in the art.

The pharmaceutical compositions according to the invention may further comprise at least one other active ingredient, such as an anticancer agent.

The present invention relates also to a pharmaceutical composition comprising:

(i) at least one compound of formula (I) such as defined above, and

(ii) at least one other active ingredient, such as an anticancer agent, as a combination product for simultaneous, separate or sequential use.

The present invention also relates to a pharmaceutical composition such as defined above for use as a drug, notably intended for the treatment of cancer.

The present invention also relates to methods for the preparation of the compounds of formula (I) according to the invention.

A first method is a method to prepare a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in which W═NR₀ with R₀≠H, comprising:

-   -   (a) reacting a compound of formula (I) in which W═NH with:         -   a compound of formula R₀-LG where R₀ represents a             (C₁-C₆)alkyl optionally substituted with CHO, CO₂H or             CO₂—((C₁-C₆)alkyl) and LG represents a leaving group to give             a compound of formula (I) in which W═NR₀ with R₀             representing a (C₁-C₆)alkyl optionally substituted with CHO,             CO₂H or CO₂—((C₁-C₆)alkyl),         -   dimethylformamide (DMF) to give a compound of formula (I) in             which W═NR₀ with R₀═CHO, or         -   a compound of formula R₀-A₁ where R₀ represents             CO₂—((C₁-C₆)alkyl) and A₁ represents a (C₁-C₆)alkoxy group             or a halogen atom (such as Cl or Br) to give a compound of             formula (I) in which W═NR₀ with R₀ representing             CO₂—((C₁-C₆)alkyl), and     -   (b) optionally salifying or solvating the compound obtained in         step (a) to give a pharmaceutically acceptable salt or solvate         of a compound of formula (I) in which W═NR₀ with R₀ as defined         above.

Step (a):

When R₀ Represents a (C₁-C₆)Alkyl Optionally Substituted with CHO, CO₂H or CO₂—((C₁-C₆)Alkyl):

The term “leaving group”, as used in the present invention, refers to a chemical group which can be easily replaced with a nucleophile during a nucleophile substitution reaction, the nucleophile being in the case of step (a) a secondary amine, i.e. a molecule carrying a group NH. Such a leaving group can be in particular a halogen atom or a sulfonate. The sulfonate is in particular a group —OSO₂—R₇ with R₇ representing a (C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)-alkyl or (C₁-C₆)-alkyl-aryl group. The sulfonate can be in particular a mesylate (CH₃—S(O₂)O—), a triflate (CF₃—S(O)₂O—) or a tosylate (p-Me-C₆H₄—S(O)₂O—).

The LG group can be in particular a halogen atom such as a bromine.

Step (a) is advantageously carried out in the presence of a base such as triethylamine.

When R₀ represents a substituted (C₁-C₆)alkyl group, the (C₁-C₆)alkyl group will be advantageously substituted with a CO₂—((C₁-C₆)alkyl) group. This group can then be hydrolysed, notably in the presence of NaOH or KOH, to give a CO₂H group (R₀ represents then a (C₁-C₆)alkyl substituted with CO₂H). A reduction step in conditions well known to the one skilled in the art allows obtaining a CHO group (R₀ represents then a (C₁-C₆)alkyl substituted with CHO).

When R₀ Represents CHO:

The reaction is advantageously performed using DMF as solvent, notably in the presence of a base such as triethylamine.

When R₀ Represents CO₂—((C₁-C₆)Alkyl):

This reaction can be carried out in conditions to prepare carbamates well known to the one skilled in the art.

Step (b):

The salification or solvatation step can be carried out by methods well known to the one skilled in the art, in particular by reaction of the compound of formula (I) obtained in step (a) with a pharmaceutically acceptable acid (organic or inorganic acid), base (organic or inorganic acid) or solvent, as defined previously.

The solvent can be notably the solvent used in the last step of the preparation of the compound according to the invention, in particular the solvent used in step (a).

Thus steps (a) and (b) can be carried out in a single step, without isolating intermediate compounds.

A second method is a method to prepare a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in which W represents NR₀,

comprising:

-   -   (1) reacting a compound of the following formula (II):

-   -    in which Q, X₁ and n1 are as defined above and W₁ represents         LG₁, NHR₈,

-   -    with a compound of the following formula (III):

-   -    in which X₂, X₃, X₄ and n2 are as defined above and W₂         represents LG₂, NHR₈,

-   -    wherein LG₁ and LG₂ represent, independently of each other, a         leaving group and R₈ represents R₀ or a N-protecting group, on         the condition that:         -   when W₁ represents LG₁, then W₂ represents NHR₈,

-   -   -    and         -   when W₁ represents NHR₈,

then W₂ represents LG₂,

-   -    and, when W₁ or W₂ represents NHR₈ with R₈ representing a         N-protecting group, deprotecting the nitrogen atom bearing the         N-protecting group, to give a compound of formula (I) as defined         above, and     -   (2) optionally salifying or solvating the compound obtained in         step (1) to give a pharmaceutically acceptable salt or solvate         of a compound of formula (I) as defined above.

Step (1):

The LG₁ and LG₂ groups can be in particular a halogen atom such as a bromine or chlorine.

The reaction between the compounds of formula (II) and (III) can be carried out in the presence of a base, such as K₂CO₃. A catalytic amount of KI can also be added to the reaction medium.

R₈ can represent in particular H or a N-protecting group, notably a N-protecting group. When W₁ or W₂ represents NHR₈ with R₈ representing H or a N-protecting group, it is possible to prepare compounds of formula (I) with W═NH.

The term “protecting group”, as used in the present invention, refers to a chemical group which selectively blocks a reactive site in a multifunctional compound so as to allow selectively performing a chemical reaction on another unprotected reactive site.

The term “N-protecting group”, as used in the present invention, refers to those groups intended to protect an amine function (notably a primary amine function) against undesirable reactions (such as a disubstitution of the primary amine function) during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)). An amine function protected by a N-protecting group can be a carbamate, an amide, a sulfonamide, an N-alkyl derivative, an amino acetal derivative, a N-benzyl derivative, an imine derivative, an enamine derivative or a N-heteroatom derivative. In particular, N-protecting groups include formyl; benzyl (Bn); —CO—R₉ such as acetyl (Ac), pivaloyl (Piv or Pv) or benzoyl (Bz); —CO₂—R₉ such as tbutyloxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc) or benzyloxycarbonyl (Cbz or Z); —SO₂—R₉ such as phenylsulfonyl or 2-nitrobenzenesulfonyl (Nos or Ns); and the like, with R₉ representing a (C₁-C₆)alkyl optionally substituted with one or several halogen atoms such as F or Cl; a (C₂-C₆)alkenyl such as an allyl; an aryl, such as a phenyl, optionally substituted with NO₂; or an aryl-(C₁-C₆)alkyl such as a benzyl.

The step of deprotecting the nitrogen atom bearing the N-protecting group can be carried out by methods well known to the one skilled in the art, notably as disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)).

The N-protecting group will be in particular 2-nitrobenzenesulfonyl (Nos or Ns). It can be deprotected in the presence of thiophenol.

The compounds of formulas (II) and (III) are either commercially available or prepared by methods well known to the one skilled in the art, notably as illustrated in the examples below.

In particular, the compound of formula (II) can be prepared by reacting a compound of formula Q-Hal with a compound of formula HX₁—(CH₂)_(n1)—W₃ where:

-   -   Q, X₁ and n1 are as defined above,     -   Hal represents a halogen atom such as Cl or Br, and     -   W₃ represents a group W₁, optionally in a protected form (W₃ can         represent notably OH).

This reaction can be performed optionally in the presence of a base.

Further steps of protection(s), deprotection(s) and/or functionalization(s) well known to the one skilled in the art can be carried out, in particular a deprotection step of the W₃ group can be carried out to introduce the W₁ function on the molecule.

When the compound of formula (III) is a compound of the following formula (IIIc):

with W₂, X₂, R₄, R₅ and n2 as defined above, this compound can be prepared by reacting a compound of the following formula (IV):

with X₂ and n2 as defined above and W₄ representing a group W₂, optionally in a protected form, with an amine of formula R₄R₅NH with R₄ and R₅ as defined above.

This reaction can be performed in the presence of a base such as K₂CO₃ or triethylamine.

The carbonyl function of the compound of formula (IV) can be activated in the form of a triazole, notably by reaction with POCl₃ and triazole (more particularly 1,2,3-triazole) preferably in the presence of a base such as triethylamine.

Thus the compound of formula (IIIc) can be prepared by:

-   -   activating the compound of formula (IV) in the form of a         triazole of the following formula (V):

-   -   with W₄, X₂ and n2 as defined above, and     -   reacting the triazole of formula (V) with the amine of formula         R₄R₅NH.

Further steps of protection(s), deprotection(s) and/or functionalization(s) well known to the one skilled in the art can be carried out, in particular a deprotection step of the W₄ group can be carried out to introduce the W₂ function on the molecule.

When the compound of formula (III) is a compound of the following formula (IIId):

with W₂, X₂, R₃ and n2 as defined above, and R₃≠H, this compound can be prepared by reacting a compound of formula (IV) as defined above with a compound of formula R₃-LG₃ with R₃ as defined above and LG₃ representing a leaving group, such as a halogen atom (e.g. Cl or Br).

This reaction can be carried out in the presence of a base, such as K₂CO₃. A catalytic amount of KI can also be added to the reaction medium.

Further steps of protection(s), deprotection(s) and/or functionalization(s) well known to the one skilled in the art can be carried out, in particular a deprotection step of the W₄ group can be carried out to introduce the W₂ function on the molecule.

The compound of formula (IV) can be prepared by reacting a compound of the following formula (VI):

where Hal represents a halogen atom such as F, with a compound of formula W₄—(CH₂)_(n2)—X₂H where W₄, X₂ and n2 are as defined above.

This reaction can be carried out in the presence of a base such as NaH.

Step (2):

The salification or solvatation step can be carried out by methods well known to the one skilled in the art, in particular by reaction of the compound of formula (I) obtained in step (1) with a pharmaceutically acceptable acid (organic or inorganic acid), base (organic or inorganic acid) or solvent, as defined previously.

The solvent can be notably the solvent used in the last step of the preparation of the compound according to the invention, in particular the solvent used in step (1).

Thus steps (1) and (2) can be carried out in a single step, without isolating intermediate compounds.

A third method is a method to prepare a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, comprising:

-   -   (A) reacting a compound of the following formula (VII):         Q-X₆  (VII)         -   in which Q is as defined above and X₆ represents a halogen             atom (e.g. Cl or Br) or —X₁—(CH₂)_(n1)—W—(CH₂)_(n2)—X₂H with             W, X₁, X₂, n1 and n2 as defined above,         -   with a compound of the following formula (VIII):

-   -   -   in which X₃ and X₄ are as defined above and X₇ represents a             halogen atom (e.g. F) or —X₂—(CH₂)_(n2)—W—(CH₂)_(n1)—X₁H             with W, X₁, X₂, n1 and n2 as defined above, on the condition             that:             -   when X₆ represents a halogen atom, then X₇ represents                 —X₂—(CH₂)_(n2)—W—(CH₂)_(n1)—X₁H, and             -   when X₆ represents —X₁—(CH₂)_(n1)—W—(CH₂)_(n2)—X₂H, then                 X₇ represents a halogen atom,         -   to give a compound of formula (I), and

    -   (B) optionally salifying or solvating the compound obtained in         step (A) to give a pharmaceutically acceptable salt or solvate         of a compound of formula (I) as defined above.

Step (A):

The reaction between the compounds of formula (VII) and (VIII) can be carried out in the presence of a base, such as K₂CO₃. A catalytic amount of KI can also be added to the reaction medium.

The compounds of formulas (VII) and (VIII) are either commercially available or prepared by methods well known to the one skilled in the art, notably as illustrated in the examples below.

In particular, the compound of formula (VII), when X₆ represents —X₁—(CH₂)_(n1)—W—(CH₂)_(n2)—X₂H, can be prepared by reacting a compound of formula Q-Hal with a compound of formula HX₁—(CH₂)_(n1)—W—(CH₂)_(n2)—X₈ where:

-   -   Q, X₁, W, n1 and n2 are as defined above,     -   Hal represents a halogen atom such as Cl or Br, and     -   X₈ represents a group X₂H, optionally in a protected form.

This reaction can be performed optionally in the presence of a base.

Further steps of protection(s), deprotection(s) and/or functionalization(s) well known to the one skilled in the art can be carried out, in particular a deprotection step of the X₈ group can be carried out to introduce the X₂H function on the molecule.

When the compound of formula (VIII) is a compound of the following formula (VIIIc):

with X₇, R₄ and R₅ as defined above, this compound can be prepared by reacting a compound of the following formula (IX):

with X₉ representing a group X₇, optionally in a protected form, with an amine of formula R₄R₅NH with R₄ and R₅ as defined above.

This reaction can be performed in the presence of a base such as K₂CO₃ or triethylamine.

The carbonyl function of the compound of formula (IX) can be activated in the form of a triazole, notably by reaction with POCl₃ and triazole (more particularly 1,2,3-triazole) preferably in the presence of a base such as triethylamine.

Thus the compound of formula (VIIIc) can be prepared by:

-   -   activating the compound of formula (IX) in the form of a         triazole of the following formula (X):

-   -   with X₉ as defined above, and     -   reacting the triazole of formula (X) with the amine of formula         R₄R₅NH.

Further steps of protection(s), deprotection(s) and/or functionalization(s) well known to the one skilled in the art can be carried out, in particular a deprotection step of the X₉ group can be carried out to introduce the X₇ group on the molecule.

When the compound of formula (VIII) is a compound of the following formula (VIIId):

with X₇ and R₃ as defined above, and R₃≠H, this compound can be prepared by reacting a compound of formula (IX) as defined above with a compound of formula R₃-LG₃ with R₃ as defined above and LG₃ representing a leaving group, such as a halogen atom (e.g. Cl or Br).

This reaction can be carried out in the presence of a base, such as K₂CO₃. A catalytic amount of KI can also be added to the reaction medium.

Further steps of protection(s), deprotection(s) and/or functionalization(s) well known to the one skilled in the art can be carried out, in particular a deprotection step of the X₉ group can be carried out to introduce the X₇ group on the molecule.

The compound of formula (IX), when X₉ represents —X₂—(CH₂)_(n2)—W—(CH₂)_(n1)—X₁₀ where X₁₀ represents X₁H optionally in a protected form, can be prepared by reacting a compound of the formula (VI) with a compound of formula HX₂—(CH₂)_(n2)—W—(CH₂)_(n1)—X₁₀ where W, X₂, X₁₀, n1 and n2 are as defined above.

This reaction can be carried out in the presence of a base such as NaH.

Step (B):

The salification or solvatation step can be carried out by methods well known to the one skilled in the art, in particular by reaction of the compound of formula (I) obtained in step (A) with a pharmaceutically acceptable acid (organic or inorganic acid), base (organic or inorganic acid) or solvent, as defined previously.

The solvent can be notably the solvent used in the last step of the preparation of the compound according to the invention, in particular the solvent used in step (A).

Thus steps (A) and (B) can be carried out in a single step, without isolating intermediate compounds.

Further steps of protection(s), deprotection(s) and/or functionalization(s) well known to the one skilled in the art can be carried out to obtained the compounds of formula (I).

The compound according to the present invention obtained by one of the methods described above can be separated from the reaction medium by methods well known to the one skilled in the art, such as by extraction, evaporation of the solvent or by precipitation or crystallisation (followed by filtration).

This compound can also be purified if necessary by methods well known to the one skilled in the art, such as by recrystallisation, by distillation, by chromatography on a column of silica gel or by high performance liquid chromatography (HPLC).

The examples which follow illustrate the invention without limiting its scope in any way.

EXAMPLES

The following abbreviations have been used in the following examples.

a.a.: Amino acid

AdoMet: S-Adenosyl-L-methionine

BSA: N,O-Bis(trimethylsilyl)acetamide

DCM: Dichloromethane

DiPEA: N,N-Diisopropylethylamine

DMAP: 4-Dimethylaminopyridine

DMF: Dimethylformamide

DMSO: Dimethylsulfoxide

EDTA: Ethylenediaminetetraacetic acid

ESI: Electrospray ionisation

HEPES: 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

HPLC: High Performance Liquid Chromatography

HRMS: High Resolution Mass Spectrometry

NMR: Nuclear Magnetic Resonance

Nos: 2-Nitrobenzenesulfonyl

PBS: Phosphate buffered saline

PBST: Phosphate buffered saline+Tween-20

RT: Room temperature

SAH: S-Adenosyl-L-homocysteine

SAM: S-Adenosyl-L-methionine

TEA: Triethylamine

TFA: Trifluoroacetic acid

TLC: Thin Layer Chromatography

Tris: Tris(hydroxymethyl)aminomethane

I. Synthesis of the Compounds According to the Invention Example 1: Compound F

4-(3-phenylpropylamino)-7-(2-chloroethoxy)quinazoline (17)

A solution of 16 (440 mg; 2.01 mmol) in thionylchloride (10 mL) and a catalytic amount of DMF was boiled for 30 min. The solvent was removed and the crude product was dissolved in a solution of phenylpropylamine (570 μL; 4.0 mmol) in DMF and the mixture was stirred at room temperature for 2 h. The mixture was diluted with ethylacetate and the organic phase was washed with a saturated solution of Na₂CO₃, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ethylacetate (0→100% ethylacetate) in cyclohexane to obtain 17 as a pale brown solid (607 mg; 1.70 mmol; yield 85%).

¹H NMR (500 MHz, CDCl₃) δ 8.58 (s, 2H, Ha1), 7.35-7.13 (m, 7H, Ha7, Ha15, Ha13 and Ha14), 6.99 (dd, J=2.4, 9.0 Hz, 1H, Ha5), 5.53 (brs, 1H, HNH), 4.22 (t, J=6.0 Hz, 2H, Hb1), 3.76 (t, J=6.0 Hz, 2H, Hb3), 3.70 (q, J=7.2 Hz, 2H, Ha9), 2.79 (t, J=7.2 Hz, 2H, Ha11), 2.28 (quint, J=6.1 Hz, 2H, Ha10), 2.07 (quint, J=7.0 Hz, 2H, Hb2).

¹³C NMR (125 MHz, CDCl₃) δ 162.0 (Ca6), 159.1 (Ca2), 156.1 (Ca1), 151.7 (Ca8), 141.7 (Ca12), 128.8 (Ca13), 128.6 (Ca14), 126.3 (Ca15), 122.0 (Ca4), 117.8 (Ca5), 109.3 (Ca3), 108.1 (Ca7), 64.7 (Cb1), 41.4 (Cb3), 41.3 (Ca9), 33.8 (Ca11), 32.1 (Cb2), 30.8 (Ca10).

HRMS-ESI (m/z) calculated for C₂₀H₂₃N₃ClO [M+H]⁺: 356.1524. Found: 356.1527.

7-((3-phthalimido)propyloxy)-4-((3-phenylpropyl)amino)quinazoline (22)

To a solution of 17 (50 mg; 141 μmol) in DMF (1 mL) was added phthalimide potassiums salt and the mixture was heated at 90° C. for 6 h. The mixture was diluted with ethylacetate and the organic phase was washed with a saturated solution of Na₂CO₃, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ethylacetate (0→100% ethylacetate) in cyclohexane to obtain 22 as a pale yellow solid (63 mg; 138 μmol; yield 98%).

¹H NMR (500 MHz; CDCl₃) δ 8.58 (s, 1H, Ha1), 7.86 (m, 2H, Hphtha), 7.74 (m, 4H, Hphtha), 7.35-7.25 (m, 6H, Ha4 and Ha13 and Ha14 and Ha15), 7.10 (d, J=2.5 Hz, 1H, Ha7), 6.92 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 5.47 (brt, J=5.1 Hz, 1H, HNH), 4.15 (t, J=6.3 Hz, 2H, Hb1), 3.96 (t, J=7.0 Hz, 2H, Hb3), 3.72 (q, J=6.7 Hz, 2H, Ha9), 2.82 (q, J=7.3 Hz, 2H, Ha11), 2.26 (quint, J=6.3 Hz, 2H, Hb2), 2.10 (quint, H=7.3 Hz, 2H, Ha10).

¹³C NMR (125 MHz, CDCl₃) δ 168.3 (Cphtha), 162.0 (Ca6), 159.0 (Ca2), 157.8 (Ca1), 151.3 (Ca8), 141.5 (Ca12), 134.0 (Cphtha), 132.1 (Cphtha), 128.7 (Ca13), 128.4 (Ca14), 126.1 (Ca15), 123.3 (Cphtha), 121.8 (Ca4), 117.9 (Ca5), 109.0 (Ca3), 107.6 (Ca7), 65.7 (Cb1), 41.1 (Ca9), 35.3 (Cb3), 33.7 (Ca11), 30.7 (Ca10), 28.0 (Cb2).

HRMS-ESI (m/z) calculated for C₂₈H₂₇N₄O₃ [M+H]⁺: 467.2078. Found: 467.2078.

7-((2-nitrobenzenesulfonamido)propyloxy)-4-((3-phenylpropyl)amino)quinazoline (23)

To a solution of 22 (60 mg; 129 μmol) in ethanol (2 mL), was added N-methylhydrazine (2004). After stirring at room temperature for 12 h, the solvent was removed and the residue was co-evaporated with toluene until the N-methylhydrazine was completely eliminated. To the crude product was added a solution of 2-nitrobenzene sulfonyl chloride (71 mg; 322 mmol) and TEA (54 μL; 387 μmol). The mixture was stirred at room temperature for 3 h, then was diluted with ethylacetate. The organic phase was washed with saturated Na₂CO₃, with brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of methanol (0→10% MeOH) in dichloromethane to obtain 23 as a pale yellow solid (61 mg; 117 μmol; yield 91%).

¹H NMR (500 MHz; CDCl₃) δ 8.59 (s, 1H, Ha1), 8.15 (m, 1H, HNos), 7.83 (m, 1H, HNos), 7.69 (m, 2H, HNos), 7.37-7.30 (m, 3H, Ha4 and Ha13), 7.22-7.15 (m, 3H, Ha14 and Ha15), 7.10-7.05 (m, 2H, Ha7 and Ha5), 5.84 (brt, J=5.3 Hz, 1H, HNH), 5.51 (brt, J=5.4 Hz, 1H, HNH), 4.13 (t, J=3.4 Hz, 2H, Hb1), 3.73 (q, J=6.3 Hz, 2H, Ha9), 3.42 (q, J=6.5 Hz, Hb3), 2.82 (q, J=6.8 Hz, 2H, Ha11), 2.17-2.07 (m, 4H, Ha10 and Hb2).

¹³C NMR (125 MHz, CDCl₃) δ 161.5 (Ca6), 159.0 (Ca2), 155.9 (Ca1), 151.3 (Ca8), 148.0 (CNos), 141.5 (Ca12), 133.6 (CNos), 133.5 (CNos), 132.8 (CNos), 130.9 (CNos), 128.7 (Ca13), 128.4 (Ca14), 126.2 (Ca15), 125.4 (CNos), 122.0 (Ca4), 117.9 (Ca5), 109.2 (Ca3), 107.6 (Ca7), 66.1 (Cb1), 41.8 (Cb3), 41.2 (Ca9), 33.7 (Ca11), 30.7 (Ca10), 28.9 (Cb2).

HRMS-ESI (m/z) calculated for C₂₉H₃₇N₈O₄ [M+H]⁺: 522.1806. Found: 522.1801.

4-((2-Hydroxyethyl)amino)quinoline (25)

A mixture of 4-chloroquinoline (360 mg; 2.21 mmol) in ethanolamine (1.5 mL; 22 mmol) was stirred at 110° C. for 3 h. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of methanol (0→10% MeOH) in dichloromethane to afford 25 as a white powder (414 mg; 2.20 mmol; quantitative yield).

¹H NMR (500 MHz, CDCl₃) δ 8.38 (d, J=5.4 Hz, 1H, Hc5), 8.19 (dd, J=0.9, 8.3 Hz, 1H, Hc8), 7.77 (dd, J=0.9, 8.3 Hz, 1H, Hc11), 7.59 (ddd, J=1.3, 6.7, 8.3 Hz, 1H, Hc10), 7.40 (ddd, J=1.3, 6.7, 8.3 Hz, 1H, Hc9), 7.07 (brt, J=5.2 Hz, 1H, HOH), 6.46 (d, J=5.4 Hz, 1H, Hc4), 4.83 (brt, J=5.5 Hz, 1H, HNHc), 3.66 (q, J=6.0 Hz, 2H, Hc1), 3.35 (q, J=5.4 Hz, 2H, Hc2).

¹³C NMR (125 MHz, CDCl₃) δ 151.1 (Cc5), 150.5 (Cc3), 148.8 (Cc6), 129.5 (Cc8), 129.1 (Cc10), 124.2 (Cc9), 122.1 (Cc11), 119.3 (Cc7), 98.6 (Cc4), 59.3 (Cc1), 45.5 (Cc2).

HRMS-ESI (m/z) calculated for C₁₁H₁₃N₂O [M+H]⁺: 189.1022. found: 189.1031.

4-((2-chloroethyl)amino)quinoline chlorhydrate (26)

25 (360 mg; 1.92 mmol) was solubilized in thionyl chloride (3 ml). The mixture was flash boiled and the solvent was removed. Toluene was added to remove the residual thionyl chloride by co-evaporation. The residue was triturated in dichloromethane and the solid was filtrated to afford 26 as a white solid (360 mg; 1.75 mmol; 91%).

¹H NMR (500 MHz; CDCl₃) δ 8.59 (d, J=5.2 Hz, 1H, Hc5), 8.00 (dd, J=0.7, 8.3 Hz, 1H, Hc8), 7.79 (d, J=8.3 Hz, 1H, Hc11), 7.65 (ddd, J=1.3, 7.9, 8.3 Hz, 1H, Hc10), 7.45 (ddd, J=1.3, 7.0, 8.3 Hz, 1H, Hc9), 6.43 (d, J=5.3 Hz, 1H, Hc4), 5.51 (brs, 1H, HNHc), 3.84 (t, J=5.8 Hz, 2H, Hc1), 3.70 (q, J=5.8 Hz, 2H, Hc1).

¹³C NMR (125 MHz, CDCl₃) δ 151.0 (Cc5), 148.9 (Cc3), 148.5 (Cc6), 130.0 (Cc8), 129.2 (Cc10), 125.0 (Cc9), 119.3 (Cc11), 118.9 (Cc7), 99.0 (Cc4), 44.4 (Cc2), 42.6 (Cc1).

HRMS-ESI (m/z) calculated for C₁₁H₁₃N₂Cl [M+H]⁺: 207.0684. found: 207.0678.

7-(3-((2-(quinolin-4-ylamino)ethyl)amino)propyloxy)-4-((3-phenylpropyl)amino)quinazoline (Compound F)

To a solution of 23 (50 mg; 96 μmol), K₂CO₃ (22 mg; 0.160 mmol) and a catalytic amount of KI in DMF (1 mL) was added 26 (40 mg; 288 μmol). The mixture was stirred at 65° C. overnight then thiophenol (24 μL; 240 mmol) was added. The mixture was stirred for a day then diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.2% of TEA (0→80% CH₃CN) to afford Compound F as a white powder (32 mg; 0.64 mmol, 67%).

¹H NMR (DMSO+MeOD) δ 8.39 (m, 2H, Hal and Hc5), 8.19-8.07 (m, 3H, Hc8, HNH and Ha4), 7.76 (dd, J=0.9, 8.4 Hz, 1H, Hell), 7.58 (ddd, J=1.3, 6.7, 8.2 Hz, 1H, Hc10), 7.39 (ddd, J=1.3, 6.7, 8.2 Hz, 1H, Hc9), 7.43-7.20 (m, 4H, Ha13 and Ha14), 7.17 (brt, J=7.1 Hz, Ha15), 7.12-7.04 (m, 3H, Ha7, HNH and Ha5), 6.47 (d, J=5.7 Hz, 1H, Hc4), 4.17 (t, J=6.2 Hz, 2H, Hb1), 3.52 (q, J=6.9 Hz, 2H, Ha9), 3.35 (m, 2H, Hc2), 2.84 (t, J=6.6 Hz, 2H, Hc1), 2.73 (t, J=6.5 Hz, 2H, Hb3), 2.67 (t, J=7.4 Hz, 2H, Ha11), 2.00-1.83 (m, 4H, Ha10 and Hb2).

¹³C NMR (DMSO+MeOD) δ 162.1 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.1 (Cc5), 150.4 (Cc3), 148.7 (Cc6), 142.2 (Ca12), 129.5 (Cc11), 129.1 (Cc10), 128.8 (Ca13), 128.7 (Ca14), 126.2 (Ca15), 124.7 (Ca4), 124.2 (Cc9), 122.0 (Cc8), 119.3 (Cc7), 117.1 (Ca5), 109.5 (Ca3), 107.8 (Ca7), 98.6 (Cc4), 66.9 (Cb1), 48 (Cc1), 46 (Cb3), 43 (Cc2), 40.6 (Ca9), 33.1 (Ca11), 30.8 (Ca10), 29.8 (Cb2).

HRMS-ESI (m/z) calculated for C₃₁H₃₅N₆O [M+H]⁺: 507.2667. found: 507.2666.

Example 2: Compounds A, B, C, D, E, T and U

4-((2-Bocaminopropyl)amino)quinoline (27) 4-((2-Bocaminobutyl)amino)quinoline (28)

A solution of N-bocaminopropane amine (2.06 g, 11.84 mmol) or N-bocaminobutane amine (2.25 g, 12 mmol), 4-chloroquinoline (1.525 g, 9.32 mmol) and DiPEA (1.8 mL, 10.3 mmol) in 12 mL of n-pentanol was stirred at reflux for 6 hours. The solvent was removed and the residue was diluted in DCM. The organic layer was washed with NaOH 2M (2×) and the aqueous phase was extracted with DCM (3×). The organics layers are collected and combined, dried over Na₂SO₄ and the solvent was removed. The residue was purified by recrystallization in toluene. 27 was obtained as a brown solid (2.02 g, 6.69 mmol; 72%) and 28 was obtained as a pale brown solid (2.35 g; 7.44 mmol; 62%).

¹H NMR (500 MHz; DMSO) δ 8.37 (d, J=5.5 Hz, 1H, Hc6), 8.19 (d, J=8.6 Hz, 1H, Hc8), 7.77 (d, J=8.39 Hz, 1H, Hc11), 7.60 (dd, J=1.2, 6.9 Hz, 1H, Hc10), 7.56 (dd, J=1.2, 6.9 Hz, 1H, Hc9), 7.17 (t, J=4.9 Hz, 1H, HNHBoc), 6.98 (t, J=5.4 Hz, 1H, HNH), 6.43 (d, J=5.4 Hz, 1H, Hc5), 3.31 (q, J=6.3 Hz, 2H, Hc3), 3.09 (q, J=6.3 Hz, 2H, Hc1), 1.81 (quint, J=7.1 Hz, 2H, Hc2), 1.38 (s, 9H, HBoc).

¹³C NMR (125 MHz, CDCl₃) δ 156.1 (CBoc), 151.1 (Cc6), 150.2 (Cc4), 148.7 (Cc12), 129.5 (Cc10), 129.1 (Cc11), 124.2 (CC9), 122.0 (Cc8), 119.2 (Cc7), 98.5 (Cc5), 78.0 (CcBoc), 40.4 (Cc3), 38.2 (Cc1), 28.7 (CcBoc), 28.6 (Cc2).

HRMS-ESI (m/z) calculated for C₁₇H₂₃N₃O₂ [M+H]+: 302.1863. Found: 302.1865.

¹H NMR (500 MHz, DMSO) δ 8.37 (d, J=5.4 Hz, 1H, Hc13), 8.22 (d, J=8.3, 1H, Hc8), 7.77 (d, J=8.3 Hz, 1H, Hc11), 7.59 (m, 1H, Hc10), 7.40 (ddd, J=1.1, 6.9, 8.9 Hz, 1H, Hc9), 7.15 (brt, J=5.2 Hz, 1H, HNH), 6.86 (brt, J=5.6 Hz, 1H, HNH), 6.43 (d, J=5.6 Hz, 1H, Hc6), 3.27 (q, J=5.6 Hz, 2H, Hc4), 2.98 (q, J=6.3 Hz, 2H, Hc1), 1.64 (quint, J=7.0 Hz, 2H, Hc3), 1.51 (quint, J=7.0 Hz, 2H, Hc2), 1.37 (s, 9H, HBoc).

¹³C NMR (125 MHz, CDCl₃) δ 156.1 (CBoc), 151.1 (Cc6), 150.2 (Cc4), 148.7 (Cc12), 129.5 (Cc10), 129.1 (Cc11), 124.2 (CC9), 122.0 (Cc8), 119.2 (Cc7), 98.5 (Cc5), 78.0 (CcBoc), 40.4 (Cc3), 38.2 (Cc1), 28.7 (CcBoc), 28.6 (Cc2).

HRMS-ESI (m/z) calculated for C₁₈H₂₆N₃O₂ [M+H]+: 316.2020. Found: 316.2018.

4-((2-aminoethyl)amino)quinoline (29) 4-((2-aminobutyl)amino)quinoline (30)

A solution of 27 (1 g; 3.32 mmol) or 28 (1.1 g; 3.48 mmol) in 10 mL of trifluoroacetic acid was stirred 1 hour at room temperature. The reaction mixture was diluted in toluene and the solvents were removed. The residue was diluted in water, basified to pH=14 with NaOH 30% and extracted with DCM. The organic layer was dried and the solvent was removed.

29 was obtained as a yellow oil (638 mg; 3.17 mmol; 96%) and 30 was obtained as a yellow oil (710 mg; 3.30 mmol; 95%).

¹H NMR (500 MHz; DMSO) δ 8.38 (d, J=4.9 Hz, 1H, Hc6), 8.17 (d, J=8.7 Hz, 1H, Hc8), 7.76 (d, J=8.3 Hz, 1H, Hc11), 7.60 (m, 1H, Hc10), 7.40 (m, 1H, Hc9), 7.25 (brs, 1H, FINE), 6.71 (brs, 2H, HNH2), 6.44 (d, J=5.9 Hz, 1H, Hc5), 3.32 (m, 2H, Hc3), 2.71 (m, 2H, Hc1), 1.76 (m, 2H, Hc2).

¹³C NMR (125 MHz, DMSO) δ 151.7 (Cc6), 150.9 (Cc4), 149.2 (Cc12), 130.0 (Cc10), 129.6 (Cc11), 124.7 (CC9), 122.6 (Cc8), 119.8 (Cc7), 99.0 (Cc5), 41.6 (Cc3), 39.0 (Cc1), 29.4 (Cc2).

HRMS-ESI (m/z) calculated for C₁₂H₁₆N₃ [M+H]⁺: 202.1339. Found: 202.1343.

¹H NMR (500 MHz; DMSO) δ 8.37 (d, J=5.2 Hz, 1H, Hc13), 8.22 (d, J=8.2 Hz, 1H, Hc8), 7.76 (d, J=8.4 Hz, 1H, Hc11), 7.59 (m, 1H, Hc10), 7.40 (m, 1H, Hc9), 7.25 (brt, J=5.2 Hz, 1H, HNH), 6.44 (d, J=5.4 Hz, 1H, Hc6), 3.34 (m, 2H, Hc4), 3.18 (m, 2H, Hc1), 1.72 (m, 2H, Hc3), 1.64 (m, 2H, Hc2).

¹³C NMR (125 MHz, DMSO) δ 151.2 (Cc13), 150.4 (Cc5), 148.8 (Cc12), 129.4 (Cc10), 129.1 (Cc11), 124.1 (CC9), 122.1 (Cc8), 119.3 (Cc7), 98.6 (Cc6), 50.7 (Cc4), 42.7 (Cc1), 28.5 (Cc3), 26.4 (Cc2).

HRMS-ESI (m/z) calculated for C₁₃H₁₈N₃ [M+H]⁺: 216.1495. Found: 216.1493.

4-((2-(2-nitrobenzenesulfonamido)propyl)amino)quinoline (31) 4-((2-(2-nitrobenzenesulfonamido)butyl)amino)quinoline (32)

To a solution of 29 (170 mg; 0.85 mmol) or 30 (182 mg; 0.85 mmol), triethylamine (378 μL; 2.72 mmol) and DMAP in catalytic amount in 4 mL of DMF was added 2-nosyl chloride (207 mg; 0.94 mmol). The reaction was stirred at room temperature overnight. The solvent was removed.

The residue containing crude product of 31 was suspended in DCM and one piece of methanol was added until the suspension was diluted. After 30 min at room temperature, 31 crystallized and it was filtrated and washed with DCM to give a yellow powder (225 mg; 0.58 mmol; 68%).

The residue containing crude product of 32 was purified by silica gel flash chromatography using a linear gradient of dicholomethane/methanol (0 to 10%) to give 32 (108 mg; 0.27 mmol; 32%) as a yellow oil.

¹H NMR (500 MHz; CDCl₃) δ 8.49 (d, J=5.4 Hz, 1H, Hc6), 8.08 (dd, J=1.7, 7.7 Hz, 1H, HNos), 7.97 (dd, J=1.0, 8.7 Hz, 1H, Hc8), 7.83-7.78 (m, 2H, Hc11 and HNos), 7.69-7.59 (m, 3H, Hc10 and HNos), 7.45 (ddd, J=1.4, 7.0 Hz, 1H, Hc9), 6.37 (d, J=5.4 Hz, 1H, Hc5), 5.64 (brs, 1H, HNH), 3.29 (brt, J=6.1 Hz, 2H, Hc3), 3.09 (q, J=6.1 Hz, 2H, Hc1), 1.99 (quint, J=6.2 Hz, 2H, Hc2).

¹³C NMR (125 MHz, CDCl₃) δ 150.6 (Cc6), 149.5 (Cc4), 148.1 (Cc12), 148.0 (CNos), 133.7 (CNos), 133.3 (CNos), 132.8 (CNos), 130.9 (CNos), 129.5 (Cc10), 129.3 (Cc11), 125.4 (CNos), 124.9 (CC9), 119.5 (Cc8), 118.8 (Cc7), 98.5 (Cc5), 78.0 (CcBoc), 40.9 (Cc3), 39.4 (Cc1), 28.1 (Cc2).

HRMS-ESI (m/z) calculated for C₁₈H₁₉N₄O₄S [M+H]⁺: 387.1122. Found: 387.1130.

¹H NMR (500 MHz; CDCl₃) δ 8.52 (d, J=5.4 Hz, 1H, Hc13), 8.08 (m, 1H, HNos), 7.99 (dd, J=1.0, 8.7 Hz, 1H, Hc8), 7.80-7.75 (m, 2H, Hc11 and HNos), 7.69-7.61 (m, 3H, Hc10 and HNos), 7.45 (ddd, J=1.4, 7.1 Hz, 1H, Hc9), 6.37 (d, J=5.5 Hz, 1H, Hc6), 5.26 (brs, 1H, HNH), 3.34 (m, 2H, Hc4), 3.21 (t, J=6.7 Hz 2H, Hc1), 1.83 (m, 2H, Hc2), 1.73 (m, 2H, Hc3).

¹³C NMR (125 MHz, CDCl₃) δ 150.6 (Cc13), 149.7 (Cc5), 148.0 (CNos), 147.9 (Cc12), 133.6 (CNos), 133.5 (CNos), 132.8 (CNos), 130.9 (CNos), 129.5 (Cc10), 129.3 (Cc11), 125.3 (CNos), 124.8 (CC9), 119.5 (Cc8), 118.6 (Cc7), 98.6 (Cc6), 43.4 (Cc4), 42.6 (Cc1), 27.3 (Cc3), 25.7 (Cc2).

HRMS-ESI (m/z) calculated for C₁₉H₂₁N₄O₄S [M+H]⁺: 401.1284. Found: 401.1280.

7-(3-((2-(quinolin-4-ylamino)propyl)amino)propyloxy)-4-((3-phenylpropyl)amino)quinazoline (Compound A) 7-(3-((2-(quinolin-4-ylamino)butyl)amino)propyloxy)-4-((3-phenylpropyl)amino)quinazoline (Compound B)

To a solution of 17 (30 mg; 85 μmol) in DMF (1 mL) was added K₂CO₃ (35 mg; 253 μmol), a catalytic amount of KI and 31 or 32 (128 μmol). The mixture was heated at 90° C. for 6 h then thiophenol (32 μL; 320 mmol) was added. The mixture was stirred at room temperature overnight then diluted with ethyl acetate. The organic phase was washed with a solution of saturated Na₂CO₃ and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.2% of TEA (0→80% CH₃CN) to afford Compound A as a white powder (26 mg; 51 μmol; 60%) or Compound B as a white powder (25 mg; 0.48 mmol; 56%).

¹H NMR (CDCl₃) δ 8.58 (s, 1H, Ha1), 8.48 (d, J=5.5 Hz, 1H, Hc6), 7.96 (d, J=8.4, 1H, Hc8), 7.85 (d, J=8.4 Hz, 1H, Ha4), 7.64 (brs, 1H, HNH), 7.58 (ddd, J=1.3, 6.8, 8.2 Hz, 1H, Hc10), 7.43-7.20 (m, 8H, Hc9, Ha15, Ha5, Hc11, Ha13 and Ha14), 7.14 (d, J=2.6 Hz, 1H, Ha7), 6.34 (d, J=5.7 Hz, 1H, Hc5), 5.72 (brt, J=5.2 Hz, 1H, HNH), 4.19 (t, J=6.0 Hz, 2H, Hb1), 3.71 (q, J=7.0 Hz, 2H, Ha9), 3.45 (t, J=6.0 Hz, 2H, Hc3), 3.00-2.92 (m, 4H, Hc1 and Hb3), 2.80 (t, J=7.4 Hz, 2H, Hal 1), 2.21-2.00 (m, 4H, Ha10 and Hb2), 1.98 (quint, J=6.0 Hz, 2H, Hc2).

¹³C NMR (CDCl₃) δ 161.8 (Ca6), 159.0 (Ca2), 156.0 (Ca1), 151.4 (Ca8), 151.1 (Cc4), 149.8 (Cc6), 146.9 (Cc12), 141.5 (Ca12), 135.0 (Cc11), 129.4 (Cc10), 128.6 (Ca13), 128.4 (Ca14), 126.1 (Ca15), 124.6 (Ca4), 122.1 (Cc9), 120.4 (Cc8), 118.8 (Cc7), 117.5 (Ca5), 109.2 (Ca3), 107.8 (Ca7), 97.9 (Cc5), 66.6 (Cb1), 49.2 (Cc1), 47.3 (Cb3), 43.6 (Cc3), 41.1 (Ca9), 33.6 (Ca11), 30.6 (Ca10), 29.3 (Cb2) 27.4 (Cc2).

HRMS-ESI (m/z) calculated for C₃₂H₃₇N₆O [M+H]+: 521.3023. Found: 521.3022.

¹H NMR (CDCl₃) δ 8.54 (s, 1H, Ha1), 8.46 (d, J=5.7 Hz, 1H, Hc13), 7.94 (d, J=8.3, 1H, Hc8), 7.81 (d, J=8.3 Hz, 1H, Ha4), 7.58 (ddd, J=1.1, 6.9, 8.3 Hz, 1H, Hc10), 7.37 (ddd, J=1.1, 6.9, 8.3 Hz, 1H, Hc9), 7.33-7.17 (m, 6H, Ha15, Hell, Ha13 and Ha14), 7.10 (d, J=2.5 Hz, 1H, Ha7), 6.90 (dd, J=2.3, 9.1 Hz, 1H, Ha5), 6.35 (d, J=5.6 Hz, 1H, Hc6), 6.00 (brs, 1H, HNH), 5.67 (brt, J=4.9 Hz, 2H, HNH), 4.14 (t, J=6.0 Hz, 2H, Hb1), 3.67 (q, J=6.5 Hz, 2H, Ha9), 3.31 (t, J=6.3 Hz, 2H, Hc4), 2.87 (t, J=6.4 Hz, Ha11), 2.80-2.72 (m, 4H, Hc1 and Hb3), 2.11-2.01 (m, 4H, Ha10 and Hb2), 1.85 (quint, J=7.2 Hz, 2H, Hc2 or Hc3), 1.71 (quint, J=7.2 Hz, 2H, Hc2 or Hc3).

¹³C NMR (CDCl₃) δ 162.0 (Ca6), 159.0 (Ca2), 155.9 (Ca1), 151.4 (Ca8), 150.4 (Cc5), 150.1 (Cc13), 147.3 (Cc12), 141.5 (Ca12), 134.9 (Cc11), 129.3 (Cc10), 128.6 (Ca13), 128.4 (Ca14), 126.1 (Ca15), 124.7 (Ca4), 122.1 (Cc9), 119.9 (Cc8), 118.6 (Cc7), 117.6 (Ca5), 109.1 (Ca3), 107.7 (Ca7), 98.5 (Cc6), 66.5 (Cb1), 49.1 (Cc1), 46.8 (Cb3), 43.1 (Cc4), 41.1 (Ca9), 33.6 (Ca11), 30.7 (Ca10), 29.1 (Cb2), 27.4 (Cc2), 26.3 (Cc3).

HRMS-ESI (m/z) calculated for C₃₃H₃₈N₆O [M+H]+: 535.3180. Found: 535.3172.

Methyl 4-((3-((4-((3-phenylpropyl)amino)quinazolin-7-yl)oxy)propyl) (3-(quinolin-4-ylamino)propyl)amino)butanoate (Compound U) Methyl 4-((3-((4-((3-phenylpropyl)amino)quinazolin-7-yl)oxy)propyl) (4-(quinolin-4-ylamino)butyl)amino)butanoate (Compound C)

To a solution of Compound A (30 mg; 59 μmol) or Compound B (26 mg; 49 μmol), K₂CO₃ (25 mg; 181 μmol), methyl 4-bromobutyrate (10 μL; 87 μmol) and a catalytic amount of KI was added. The mixture was stirred at 90° C. overnight then diluted with ethylacetate. The organic phase was washed with a saturated solution of NaHCO₃ and brine. The organic phase was dried over Na₂SO₄ and the solvent was removed. The residue was purified by silica gel flash chromatography using a linear gradient of methanol (0→10% MeOH) in dichloromethane.

Compound U (Methyl ester of Compound D) was obtained as a white amorphous solid (16 mg; 26 μmol; 44%) and Compound C (Methyl ester of Compound T) was obtained as a white amorphous solid (14 mg; 26 μmol; 45%).

¹H NMR (CDCl₃) δ 8.52 (s, 1H, Ha1), 8.40 (d, J=6.0 Hz, 1H, Hc6), 7.96 (d, J=8.4, 1H, Hc8), 7.79 (d, J=8.4 Hz, 1H, Ha4), 7.56 (ddd, J=1.0, 6.0, 8.4 Hz, 1H, Hc10), 7.43-7.20 (m, 8H, Hc9, Ha15, HNH, Hc11, Ha13 and Ha14), 7.10-7.02 (m, 2H, Ha7 and HNH), 7.14 (dd, J=2.6, 9.0 Hz, 1H, Ha5), 6.31 (d, J=5.7 Hz, 1H, Hc5), 5.92 (m, 1H, HNH), 4.06 (t, J=6.0 Hz, 2H, Hb1), 3.67 (q, J=6.3 Hz, 2H, Ha9), 3.62 (s, 3H, HMe), 3.37 (q, J=6.0 Hz, 2H, Hc3), 2.76 (t, J=7.4 Hz, 2H, Hb3), 2.71 (t, J=7.2 Hz, 2H, Hb4), 2.65 (t, J=6.0 Hz, 2H, Hc1), 2.55 (t, J=7.2 Hz, 2H, Hb6), 2.35 (t, J=7.4 Hz, 2H, Ha11), 2.06 (quint, J=7.4 Hz, 2H, Ha10), 2.01-1.80 (m, 6H, Hb5, Hb2 and Hc2).

¹³C NMR (CDCl₃) δ 173.9 (Cb7), 161.9 (Ca6), 159.1 (Ca2), 155.9 (Ca1), 151.3 (Ca8), 151.2 (Cc4), 148.7 (Cc6), 145.9 (Cc12), 141.6 (Ca12), 129.8 (Cc11), 128.6 (Ca13), 128.4 (Ca14), 127.7 (Cc10), 126.0 (Ca15), 124.9 (Ca4), 122.4 (Cc9), 120.2 (Cc8), 118.4 (Cc7), 117.2 (Ca5), 109.1 (Ca3), 107.8 (Ca7), 98.0 (Cc5), 66.0 (Cb1), 53.5 (Cc1), 52.8 (Cb3), 51.6 (CMe), 50.5 (Cb4), 43.0 (Cc3), 41.1 (Ca9), 33.6 (Ca11), 31.7 (Cb6), 30.7 (Ca10), 26.5 (Cb2) 25.4 (Cc2), 22.0 (Cb5).

HRMS-ESI (m/z) calculated for C₃₇H₄₅N₆O3 [M+H]+: 621.3548. Found: 621.3560.

¹H NMR (CDCl₃) δ 8.50 (s, 1H, Ha1), 8.47 (d, J=5.4 Hz, 1H, Hc13), 7.94 (d, J=7.4, 1H, Hc8), 7.69 (d, J=8.3 Hz, 1H, Ha4), 7.56 (t, J=7.4 Hz, 1H, Hc10), 7.34 (t, J=7.4 Hz, 1H, Hc9), 7.30-7.22 (m, 3H, Ha13 and Hell) 7.21-7.12 (m, 3H, Ha15 and Ha14), 7.11 (d, J=2.5 Hz, 1H, Ha7), 6.90 (dd, J=2.5, 8.9 Hz, 1H, Ha5), 6.31 (d, J=5.3 Hz, 1H, Hc6), 5.65 (m, 1H, HNH), 5.30 (m, 1H, HNH), 4.10 (t, J=6.1 Hz, 2H, Hb1), 3.67-3.60 (m, 5H, Ha9 and HMe), 3.19 (q, J=7.0 Hz, 2H, Hc4), 2.75 (t, J=7.4 Hz, 2H, Hc1), 2.59 (t, J=6.6 Hz, 2H, Hb6), 2.55 (m, 4H, Hb4 and Hb3), 2.32 (t, J=7.4 Hz, 2H, Hal 1), 2.03 (quint, J=7.4 Hz, 2H, Hal 0), 1.91 (quint, J=6.3 Hz, 2H, Hb5), 1.80-1.68 (m, 4H, Hb2 and Hc2), 1.56 (quint, J=7.3 Hz, 2H, Hc3).

¹³C NMR (CDCl₃) δ 174.1 (Cb7), 162.2 (Ca6), 159.0 (Ca2), 155.9 (Ca1), 151.4 (Cc5), 150.5 (Cc13), 149.7 (Ca8), 147.9 (Cc12), 141.6 (Ca12), 129.3 (Cc11), 129.1 (Cc10), 128.6 (Ca13), 128.4 (Ca14), 126.0 (Ca15), 124.5 (Ca4), 122.1 (Cc9), 119.6 (Cc8), 118.6 (Cc7), 117.6 (Ca5), 109.0 (Ca3), 107.6 (Ca7), 98.5 (Cc6), 65.9 (Cb1), 53.5 (Cc1), 53.1 (Cb3), 51.5 (CMe), 49.9 (Cb4), 43.2 (Cc4), 41.1 (Ca9), 33.6 (Ca11), 31.7 (Cb6), 30.7 (Ca10), 26.8 (Cc3), 26.6 (Cb2), 25.2 (Cc2), 22.4 (Cb5).

HRMS-ESI (m/z) calculated for C₃₈H₄₇N₆O3 [M+H]+: 635.3704. Found: 635.3709.

N-(3-((4-((3-phenylpropyl)amino)quinazolin-7-yl)oxy)propyl)-N-(3-(quinolin-4-ylamino)propyl)formamide (Compound E)

Compound E is a by-product isolated from the synthesis of Compound U and was obtained as a white amorphous solid (8 mg; 15 μmol; 25%).

¹H NMR (DMSO) δ 8.42-8.35 (m, 2H, Hal and Hc6), 8.24-8.10 (m, 3H, Hc8, Ha4 and HNH), 8.08 (d, J=8.9 Hz, 1H, Hb4), 7.78 (d, J=8.5 Hz, Hc11), 7.63-7.58 (m, 1H, Hc10), 7.44-7.39 (m, 1H, Hc9), 7.32-7.22 (m, 4H, Ha13 and Ha14), 7.21-7.11 (m, 2H, Ha15 and HNH), 7.10-7.02 (m, 2H, Ha5 and Ha7), 6.45 (t, J=5.0 Hz, 1H, Hc5), 4.09 (m, 2H, Hb1), 3.57-3.31 (m, 6H, Hc3, Hc1 and Hb3), 3.30-3.22 (m, 1H, Ha9a), 2.71 (t, J=7.4 Hz, 2H, Ha11), 2.05-1.87 (m, 6H, Hc2, Ha10 and Hb2).

¹³C NMR (DMSO) δ 163.5-163.4 (Cb4), 161.9-161.8 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc6), 150.3-150.2 (Cc4), 148.8-148.7 (Cc12), 142.2 (Ca12), 129.5-129.4 (Cc11), 129.1 (Cc10), 128.8 (Ca13), 128.7 (Ca14), 126.2 (Ca15), 124.8-124-7 (Ca4), 124.2-124.2 (Cc9), 122.2-122.0 (Cc8), 119.3 (Cc7), 117.2-117.1 (Ca5), 109.7-109.6 (Ca3), 107.9-107.8 (Ca7), 98.7-98.6 (Cc5), 66.1-65.4 (Cb1), 46.1 (Cc1), 45.9 (Cb3), 40.5 (Cc3), 39.1 (Ca9), 33.1 (Ca11), 30.8 (Ca10), 27.9-27.3 (Cb2), 27.1-26.3 (Cc2).

HRMS-ESI (m/z) calculated for C₃₃H₃₇N₆O2 [M+H]+: 549.2973. Found: 549.2972.

4-((3-((4-((3-phenylpropyl)amino)quinazolin-7-yl)oxy)propyl)(3-(quinolin-4-ylamino)propyl)amino)butanoic acid (Compound D) 4-((3-((4-((3-phenylpropyl)amino)quinazolin-7-yl)oxy)propyl)(4-(quinolin-4-ylamino)butyl)amino)butanoic acid (Compound T)

To a solution of Compound U (16 mg; 26 μmol) or Compound C (14 mg; 22 μmol) in dioxane (0.5 mL) was added a 0.5N solution of NaOH (0.5 mL). The mixture was stirred at room temperature for 6 h then was neutralized using a 0.5N HCl solution (0.5 mL). The solvent was removed and the residue was triturated in methanol. The mixture was filtrated and the filtrate was purified by reversed phase HPLC using a linear acetonitrile gradient (0→80% CH₃CN).

Compound D was obtained as pale yellow viscous oil (12 mg; 20 μmol; 78%) and Compound T was obtained as pale yellow viscous oil (11 mg; 17 μmol; 79%).

¹H NMR (DMSO+MeOD) δ 8.38 (s, 1H, Ha1), 8.33 (d, J=5.3 Hz, 1H, Hc6), 8.1 (d, J=7.7 Hz, 1H, Hc8), 8.13 (d, J=8.9 Hz, 1H, Ha4), 8.09 (t, J=5.3 Hz, 1H, HNH), 7.76 (dd, J=0.8, 8.3 Hz, 1H, Hc11), 7.58 (ddd, J=1.0, 6.0, 8.4 Hz, 1H, Hc10), 7.39 (ddd, J=1.0, 6.0, 8.4 Hz, 1H, Hc9), 7.32-7.21 (m, 4H, Ha13 and Ha14), 7.22-7.12 (m, 2H, Ha15, HNH), 7.10-7.02 (m, 2H, Ha7 and Ha5), 6.37 (d, J=5.7 Hz, 1H, Hc5), 4.12 (t, J=6.1 Hz, 2H, Hb1), 3.53 (q, J=6.3 Hz, 2H, Ha9), 3.27 (q, J=5.6 Hz, 2H, Hc3), 2.67 (t, J=7.5 Hz, 2H, Hc1), 2.60 (t, J=6.7 Hz, 2H, Hb4), 2.56 (t, J=6.7 Hz, 2H, Hb3), 2.46 (t, J=6.7 Hz, 2H, Hb6), 2.22 (t, J=7.1 Hz, 2H, Ha11), 1.99-1.86 (m, 4H, Hb2 and Ha10), 1.81 (quint, J=7.4 Hz, 2H, Hb5), 1.65 (quint, J=7.4 Hz, 2H, Hc2).

¹³C NMR (DMSO+MeOD) δ 175.1 (Cb7), 162.1 (Ca6), 159.5 (Ca2), 156.0 (Ca1), 151.8 (Ca8), 151.0 (Cc6), 150.4 (Cc4), 148.6 (Cc12), 142.2 (Ca12), 129.3 (Cc11), 129.1 (Cc10), 128.8 (Ca13), 128.7 (Ca14), 126.1 (Ca15), 124.7 (Ca4), 124.2 (Cc8), 122.1 (Cc9), 119.3 (Cc7), 117.1 (Ca5), 109.5 (Ca3), 107.8 (Ca7), 98.5 (Cc5), 66.4 (Cb1), 53.4 (Cc1), 51.8 (Cb3), 50.2 (Cb4), 41.2 (Ca9), 40.6 (Cc3), 33.1 (Ca11), 32.6 (Cb6), 30.8 (Ca10), 26.7 (Cb2), 25.8 (Cc2), 22.6 (Cb5).

HRMS-ESI (m/z) calculated for C₃₆H₄₃N₆O₃ [M+H]+: 607.3391. Found: 607.3391.

¹H NMR (DMSO+MeOD) δ 8.37 (s, 1H, Ha1), 8.33 (d, J=5.5 Hz, 1H, Hc13), 8.19 (d, J=7.9 Hz, 1H, Hc8), 8.13 (d, J=8.9 Hz, 1H, Ha4), 8.09 (t, J=5.3 Hz, 1H, HNH), 7.75 (dd, J=0.9, 8.4 Hz, 1H, Hell), 7.57 (ddd, J=1.2, 6.7, 8.2 Hz, 1H, Hc10), 7.38 (ddd, J=1.2, 6.7, 8.2 Hz, 1H, Hc9), 7.29-7.20 (m, 4H, Ha13 and Ha14), 7.19-7.11 (m, 2H, Ha15, HNH), 7.09 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 7.03 (d, J=2.5 Hz, 1H, Ha7), 6.35 (d, J=5.3 Hz, 1H, Hc5), 4.11 (t, J=6.1 Hz, 2H, Hb1), 3.52 (q, J=7.0 Hz, 2H, Ha9), 3.19 (m, 2H, Hc4), 2.67 (t, J=7.5 Hz, 2H, Hc1), 2.56 (t, J=6.7 Hz, 2H, Hb6), 2.48-2.39 (m, 4H, Hb4 and Hb3), 2.22 (t, J=7.1 Hz, 2H, Ha11), 1.91 (quint, J=7.4 Hz, 2H, Ha10), 1.86 (quint, J=6.3 Hz, 2H, Hb5), 1.71-1.58 (m, 4H, Hb2 and Hc2), 1.51 (quint, J=7.6 Hz, 2H, Hc3).

¹³C NMR (DMSO+MeOD) δ 175.2 (Cb7), 162.0 (Ca6), 159.5 (Ca2), 156.0 (Ca1), 151.7 (Cc5), 151.0 (Cc13), 150.4 (Ca8), 148.6 (Cc12), 142.2 (Ca12), 129.3 (Cc11), 129.1 (Cc10), 128.8 (Ca13), 128.7 (Ca14), 126.1 (Ca15), 124.7 (Ca4), 124.1 (Cc8), 122.2 (Cc9), 119.2 (Cc7), 117.2 (Ca5), 109.5 (Ca3), 107.8 (Ca7), 98.5 (Cc6), 65.4 (Cb1), 53.6 (Cc1), 53.4 (Cb3), 50.1 (CMe), 46.0 (Cb4), 42.8 (Cc4), 40.5 (Ca9), 33.2 (Ca11), 32.7 (Cb6), 30.8 (Ca10), 26.7 (Cc3), 26.1 (Cb2), 24.7 (Cc2), 22.6 (Cb5).

HRMS-ESI (m/z) calculated for C₃₇H₄₅N₆O₃ [M+H]+: 621.3548. Found: 621.3545.

Example 3: Compound G

7-O—((N-Boc)piperidin-4-ylmethoxy)quinazolinone (43)

To a mixture of (N-Boc)piperidin-4-ylmethanol (1.12 g; 5.2 mmol) in DMF (2 mL) at 0° C. under argon was added sodium hydride (125 mg, 5.2 mmol). The mixture was stirred for 15 min at 0° C. then 42 (162 mg; 1 mmol) was added portion wise. The mixture was stirred at 0° C. for 10 min then at room temperature for 10 min, at 60° C. for 15 min and finally at 110° C. for 2 h. The reaction mixture was diluted with ethylacetate and washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was removed. The crude product was purified by silica gel flash chromatography using a linear gradient of ethylacetate (0→100% AcOEt) in cyclohexane to afford 43 as a white powder (241 mg; 0.67 μmol; 67%).

¹H NMR (500 MHz; CDCl₃) δ 11.50 (s, 1H, HNH), 8.19 (d, 1H, J=8.9, Ha4), 8.7 (s, 1H, Ha1), 7.12-7.07 (m, 2H, Ha7 and Ha5), 4.18 (sb, 2H, Hb4), 3.94 (d, J=6.8, 2H, Hb1), 2.76 (m, 2H, Hb4), 2.03 (m, 1H, Hb2), 1.84 (m, 2H, Hb3), 1.47 (s, 9H, HBoc), 1.38-1.11 (m, 2H, Hb3).

¹³C NMR (125 MHz, CDCl₃) δ 164.6 (Ca6), 162.3 (Ca2), 155.2 (CBoc), 151.5 (Ca8), 144.3 (Ca1), 128.3 (Ca4), 118.0 (Ca5), 116.3 (Ca3), 109.4 (Ca7), 79.9 (CBoc), 73.0 (Cb1), 47.0 (Cb4), 36.3 (Cb2), 29.1 (Cb3), 28.8 (CBoc).

HRMS-ESI (m/z) calculated for C₁₉H₂₆N₃O₄[M+H]⁺: 360.1918. found: 360.1911.

4-((3-phenylpropyl)amino)-7-(O—((N-Boc)piperidin-4-ylmethoxy))quinazoline (44)

To a solution of triazole (280 mg; 4 mmol) and POCl₃ (120 μl; 1.32 mmol) in 3 mL of acetonitrile at 0° C. was added TEA (5604) dropwise. The reaction mixture was stirred at 0° C. for 40 min then 30 min at room temperature. 43 (215 mg; 0.6 mmol) was added and the mixture was vigorously stirred at room temperature overnight. The reaction was followed by TLC using ethyl acetate as eluent. The mixture was refluxed for 1 h to reach completion. After complete consumption of the starting material, the solvent was removed and the residue was taken off with ethylacetate and washed with water and brine, and dried over sodium sulfate. The solvent was removed and the residue was solubilized in DMF (2 mL). Phenylpropylamine (130 μL; 1.0 mmol) and TEA (167 μL; 1.2 mmol) were added and the mixture was stirred for 3 h at room temperature. The mixture was diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ethyl acetate (0→100% AcOEt) in cyclohexane to afford 44 as a white powder (232 mg; 0.49 mmol; 81%).

¹H NMR (500 MHz; CDCl₃) δ 8.57 (s, 1H, Ha1), 7.33-7.28 (m, 3H, Ha4 and Ha13), 7.25-7.20 (m, 3H, Ha15 and Ha14), 7.12 (d, J=2.6 Hz, 1H, Ha7), 7.00 (dd, J=2.6, 9.5 Hz, 1H, Ha5), 5.44 (brt, J=5.2, 1H, HNH), 4.17 (brs, 2H, Hb4eq), 3.92 (d, J=6.3 Hz, 2H, Hb1), 3.70 (q, J=7.2 Hz, 2H, Ha9), 2.79 (t, 2H, J=7.3 Hz, Ha11), 2.75 (brt, J=11.2 Hz, 2H, Hb4ax), 2.09 (quint, J=7.3 Hz, 2H, Ha10), 2.01 (m, 1H, Hb2), 1.83 (d, J=12.3 Hz, 2H, Hb3eq), 1.47 (s, 9H, HBoc), 1.31 (dq, J=4.5-12.3 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz; CDCl₃) δ 162.9 (Ca6), 159.2 (Ca2), 156.1 (Ca1), 155.0 (CBoc), 151.7 (Ca8), 141.7 (Ca12), 128.8 (Ca13), 128.6 (Ca14), 126.3 (Ca15), 122.0 (Ca4) 118.0 (Ca5), 109.1 (Ca3), 108.0 (Ca7), 79.6 (CBoc), 72.6 (Cb1), 43.7 (Cb4), 41.3 (Ca9), 36.1 (Cb2), 33.8 (Ca11), 30.9 (Ca10), 29.0 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated for C₁₉H₂₆N₃O₄[M+H]⁺: 477.2860. found: 477.2861.

4-((3-phenylpropyl)amino)-7-O-(piperidin-4-ylmethoxy)quinazoline (45)

A mixture of 44 (220 mg; 0.46 mmol) in TFA was stirred for 1 h at room temperature. TFA was removed. The residue was diluted with dichloromethane and the organic phase was washed with saturated Na₂CO₃. The solvent was removed and 45 was obtained as pale blue foam (165 mg; 0.44 mmol; 96%).

¹H NMR (DMSO) δ 9.94 (brs, 1H, HNH), 8.79 (s, 1H, Ha1), 8.4 (d, J=9.3 Hz, 1H, Ha4), 7.43-7.13 (m, 7H, Ha5, Ha7, Ha13, Ha14 and Ha15), 4.06 (d, J=6.2 Hz, 2H, Hb1), 3.70 (q, J=7.2 Hz, 2H, Ha9), 3.34 (brd, J=12.6 Hz, 2H, Hb4eq), 2.94 (brt, J=11.5 Hz, 2H, Hb4ax), 2.69 (t, J=7.3 Hz, 2H, Ha11), 2.15 (m, 1H, Hb2), 2.00 (quint, 2H, J=7.3 Hz, Ha10), 1.95 (brd, 2H, Hb3eq), 1.53 (dq, J=4.0-15.0 Hz, 2H, Hb3ax).

¹³C NMR (DMSO) δ 164.5 (Ca6), 160.8 (Ca2), 152.5 (Ca1), 142.3 (Ca8), 141.7 (Ca12), 129.3 (Ca13), 129.2 (Ca14), 127.2 (Ca4), 126.7 (Ca15), 119.1 (Ca5), 107.9 (Ca3), 102.6 (Ca7), 72.9 (Cb1), 43.6 (Cb4), 42.2 (Ca9), 33.8 (Cb2), 33.4 (Ca11), 30.8 (Ca10), 26.0 (Cb3).

HRMS-ESI (m/z) calculated for C₁₉H₂₆N₃O₄ [M+H]⁺: 377.2336. found: 377.2303.

4-((3-phenylpropyl)amino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (Compound G)

To a solution of 45 (30 mg; 80 μmol), K₂CO₃ (22 mg; 160 μmol) and a catalytic amount of KI in DMF (1 mL) was added 26 (33 mg; 160 μmol). The mixture was stirred at 65° C. overnight then was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound G as a white powder (35 mg; 64 μmol; 80%).

¹H NMR (500 MHz; CDCl₃) δ 8.58 (s, 1H, Ha1), 8.56 (d, J=5.4 Hz, 1H, Hc5), 7.98 (dd, J=0.7, 8.4 Hz, 1H, Hc8), 7.76 (dd, J=0.7, 8.4 Hz, 1H, Hc11), 7.63 (ddd, J=1.2, 6.9, 8.2 Hz, 1H, Hc10), 7.46 (ddd, J=1.2, 6.9, 8.2 Hz, 1H, Hc9), 7.34-7.28 (m, 3H, Ha4 and Ha13), 7.25-7.20 (m, 3H, Ha15 and Ha14), 7.13 (d, J=2.5 Hz, 1H, Ha7), 7.00 (dd, J=2.6, 5.1 Hz, 1H, 9.1 Hz, Ha5), 6.40 (d, J=5.1 Hz, 1H, Hc4), 5.96 (brt, J=4.5 Hz, 1H, HNHc), 5.48 (brt, J=5.1 Hz, 1H, HNHa), 3.96 (d, J=6.1 Hz, 2H, Hb1), 3.70 (q, J=7.2 Hz, 2H, Ha9), 3.34 (q, J=5.2 Hz, 2H, Hc2), 3.00 (brd, J=12.0 Hz, 2H, Hb4eq), 2.75 (m, 4H, Ha11 and Hc1), 2.14 (dt, J=2.1 Hz, 2H, Hb4ax), 2.09 (quint, J=7.2 Hz, 2H, Ha10), 1.94 (m, 1H, Hb2), 1.91 (d, J=12.3 Hz, 2H, Hb3eq), 1.47 (dq, J=3.4, 12.5 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 161.6 (Ca6), 158.4 (Ca2), 155.3 (Ca1), 151.0 (Ca8), 150.5 (Cc5), 149.1 (Cc3), 147.8 (Cc6), 140.9 (Ca12), 129.3 (Cc8), 128.3 (Cc10), 128.0 (Ca13), 127.8 (Ca14), 125.5 (Ca15), 124.0 (Cc9), 121.2 (Ca4), 118.8 (Cc11), 118.3 (Cc7), 117.2 (Ca5), 108.3 (Ca3), 107.2 (Ca7), 98.4 (Cc4), 72.0 (Cb1), 55.3 (Cc1), 52.3 (Cb4), 40.5 (Ca9), 38.6 (Cc2), 35.0 (Cb2), 33.0 (Ca11), 30.1 (Ca10), 28.6 (Cb3).

HRMS-ESI (m/z) calculated for C₁₉H₂₆N₃O₄ [M+H]⁺:547.3180. found: 547.3171.

Example 4: Compound O

Compound O was synthesized following the same procedure as for Compound G.

4-(3-phenethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (Compound O)

To a solution of 4-(2-phenethylamino)-7-(piperidin-4-ylmethoxy)quinazoline (30 mg; 0.08 mmol), K₂CO₃ (23 mg; 0.16 mmol) and a catalytic amount of KI in DMF (1.5 mL) was added 26 (40 mg; 0.16 mmol). The mixture was stirred at 65° C. for 24 hours. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound O as a white powder (28 mg; 0.05 mmol; 64%).

¹H NMR (500 MHz; CDCl₃) δ 8.64 (s, 1H, Ha1), 8.59 (d, J=5.6 Hz, 1H, Hc5), 8.04 (d, J=8.2 Hz, 1H, Hc8), 7.80 (d, J=0.7, 8.4 Hz, 1H, Hc11), 7.68 (ddd, J=1.3, 6.9, 8.3 Hz, 1H, Hc10), 7.51 (ddd, J=1.1, 6.7, 8.3 Hz, 1H, Hc9), 7.44 (d, J=9.28 Hz, 1H, Ha4), 7.38-7.33 (m, 2H, Ha12), 7.31-7.26 (m, 3H, Ha14 and Ha13), 7.18 (d, J=2.6 Hz, 1H, Ha7), 7.05 (dd, J=2.6, 9.0 Hz, 1H, Ha5), 6.43 (d, J=5.4 Hz, 1H, Hc4), 6.15 (brs, 1H, HNHc), 5.60 (brt, J=5.7, 1H, HNHa), 4.00 (d, J=6.2 Hz, 2H, Hb1), 3.70 (dd, J=6.7, 12.2 Hz, 2H, Ha9), 3.38 (q, J=5.2 Hz, 2H, Hc2), 3.08-3.00 (m, 4H, Hb4eq and Hc1), 2.83 (t, J=6.2 Hz, Ha10), 2.18 (dt, J=1.3, 11.6 Hz, 2H, Hb4ax), 2.09-1.89 (m, 3H, Hb2 and Hb3eq), 1.47 (dq, J=3.0-12.5 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 162.2 (Ca6), 159.0 (Ca2), 156.0 (Ca1), 151.7 (Ca8), 150.3 (Cc5), 150.2 (Cc3), 147.5 (Cc6), 138.9 (Ca12), 129.4 (Cc8), 129.1 (Cc10), 128.9 (Ca12), 128.8 (Ca13), 126.6 (Ca14), 124.9 (Cc9), 121.8 (Ca4), 119.5 (Cc11), 118.7 (Cc7), 118.1 (Ca5), 109.2 (Ca3), 107.9 (Ca7), 98.8 (Cc4), 72.6 (Cb1), 55.8 (Cc1), 52.9 (Cb4), 42.1 (Ca9), 39.1 (Cc2), 35.6 (Cb2), 35.3 (Ca10), 29.2 (Cb3).

HRMS-ESI (m/z) calculated for C₃₃H₃₇N₆O [M+H]⁺: 533.3023. found: 533.3023.

Example 5: Compound P

Compound P was synthesized following the same procedure as for Compound G.

4-(3-benzylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (Compound P)

To a solution of 4-(2-benzylamino)-7-(piperidin-4-ylmethoxy)quinazoline (30 mg; 0.086 mmol), K₂CO₃ (24 mg; 0.172 mmol) and a catalytic amount of KI in DMF (1.5 mL) was added 26 (42 mg; 0.172 mmol). The mixture was stirred at 65° C. overnight. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound P as a white powder (30 mg; 0.058 mmol; 68%).

¹H NMR (500 MHz; CDCl₃) δ 8.66 (s, 1H, Ha1), 8.58 (d, J=5.1 Hz, 1H, Hc5), 8.00 (dd, J=0.7, 8.5 Hz, 1H, Hc8), 7.79 (dd, J=0.7, 8.5 Hz, 1H, Hc11), 7.61 (d, J=8.9 Hz, 1H, Ha4), 7.66 (ddd, J=1.4, 6.8, 8.3 Hz, 1H, Hc10), 7.48 (ddd, J=1.4, 6.8, 8.3 Hz, 1H, Hc9), 7.45-7.32 (m, 5H, Ha11 and Ha12 and Ha13), 7.20 (d, J=2.4 Hz, 1H, Ha7), 7.08 (dd, J=2.4, 1H, 9.1 Hz, Ha5), 6.42 (d, J=5.3 Hz, 1H, Hc4), 5.96 (brt, J=4.1, 1H, HNHc), 5.87 (m, 1H, HNHa), 4.87 (d, J=5.2 Hz, Ha9), 4.00 (d, J=6.1 Hz, 2H, Hb1), 3.36 (q, J=5.2 Hz, 2H, Hc2), 3.03 (brd, J=11.7 Hz, 2H, Hb4eq), 2.81 (t, J=6.0 Hz, 2H, Ha11), 2.16 (dt, J=1.2, 11.8 Hz, 2H, Hb4ax), 2.01-1.89 (m, 3H, Hb2 and Hb3eq), 1.50 (dq, J=3.6-12.1 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 162.3 (Ca6), 158.9 (Ca2), 156.0 (Ca1), 151.8 (Ca8), 151.1 (Cc5), 149.8 (Cc3), 148.3 (Cc6), 138.2 (Ca10), 129.8 (Cc8), 129.0 (Cc10), 128.8 (Ca12), 128.0 (Ca11), 127.8 (Ca13), 124.6 (Cc9), 122.0 (Ca4), 119.5 (Cc11), 118.9 (Cc7), 118.1 (Ca5), 109.0 (Ca3), 107.9 (Ca7), 99.0 (Cc4), 72.7 (Cb1), 55.9 (Cc1), 52.9 (Cb4), 45.3 (Ca9), 39.2 (Cc2), 35.7 (Cb2), 29.2 (Cb3).

HRMS-ESI (m/z) calculated for C₃₂H₃₅N₆O [M+H]⁺: 519.2867. Found: 519.2870.

Example 6: Compound H

Compound H was synthesized following the same procedure as for Compound G.

4-propylamino-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (Compound H)

To a solution of 4-propylamino-7-O-(piperidin-4-ylmethoxy)quinazoline (10 mg; 33 μmol), K₂CO₃ (9 mg; 66 μmol) and a catalytic amount of KI in DMF (0.5 mL) was added 26 (14 mg; 67 μmol). The mixture was stirred at 65° C. overnight then was diluted with ethylacetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.2% of TEA (0→80% CH₃CN) to afford Compound H as a white powder (12.0 mg; 26 μmol; 78%).

¹H NMR (DMSO) δ 8.39 (d, J=5.3 Hz, 1H, Hc5), 8.37 (s, 1H, Ha1), 8.17-8.11 (m, 2H, Ha4 and Hc8), 8.07 (brt, J=5.3, 1H, HNHa), 7.77 (dd, J=1.1, 8.4 Hz, 1H, Hc11), 7.60 (ddd, J=1.3, 6.9, 8.2 Hz, 1H, Hc10), 7.41 (ddd, J=1.3, 6.9, 8.2 Hz, 1H, Hc9), 7.09 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 7.04 (m, 1H, Ha7), 6.47 (d, J=5.8 Hz, 1H, Hc4), 3.96 (d, J=5.85 Hz, 2H, Hb1), 3.45 (q, J=5.8 Hz, 2H, Ha9), 3.40 (q, J=6.2 Hz, 2H, Hc2), 3.00 (brd, J=10.1 Hz, 2H, Hb4eq), 2.62 (t, J=7.1 Hz, 2H, Hc1), 2.04 (t, J=10.1 Hz, 2H, Hb4ax), 1.91 (m, 3H, Hb3eq and Hb2), 1.63 (sext, J=7.4 Hz, 2H, Ha10), 1.36 (dq, J=3.0-12.6 Hz, 2H, Hb3ax), 0.91 (t, J=7.3 Hz, 3H, Ha11).

¹³C NMR (DMSO) δ 162.1 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc3), 148.2 (Cc6), 129.5 (Cc11), 129.1 (Cc10), 124.7 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 119.2 (Cc7), 117.1 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 42.6 (Ca9), 40.6 (Cc2), 35.7 (Cb2), 29.0 (Cb3), 22.4 (Ca10), 11.9 (Ca11).

HRMS-ESI (m/z) calculated for C₂₈H₃₅N₆O [M+H]⁺: 471.2867. found: 471.2876.

Example 7: Compound I

Compound I was synthesized following the same procedure as for Compound G.

4-amino-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (Compound I)

To a solution of 4-amino-7-(piperidin-4-ylmethoxy)quinazoline (10 mg; 0.039 mmol), K₂CO₃ (21 mg; 0.078 mmol) and a catalytic amount of KI in DMF (0.5 mL) was added 26 (16 mg, 0.078 mmol). The mixture was stirred at 65° C. overnight then was diluted with ethylacetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound I as a white powder (11.4 mg; 0.027 mmol; 68%).

¹H NMR (DMSO) δ 8.39 (d, J=5.5 Hz, 1H, Hc5), 8.29 (s, 1H, Ha1), 8.15 (m, 3H, Hc8 and HNH₂), 8.10 (d, J=9.0, 1H, Ha4), 7.77 (dd, J=1.0 Hz, 8.4 Hz, 1H, Hc11), 7.60 (ddd, J=1.2, 6.8, 8.2 Hz, 1H, Hc10), 7.42 (ddd, J=1.2, 6.8, 8.2 Hz, 1H, Hc9), 7.08 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 7.06-7.01 (m, 2H, Ha7 and HNH), 6.47 (d, J=5.3 Hz, 1H, Hc4), 3.97 (d, J=5.8 Hz, 2H, Hb1), 3.41 (q, J=6.4 Hz, 2H, Hc2), 3.00 (brd, J=11.0 Hz, 2H, Hb4eq), 2.62 (t, J=6.2 Hz, 2H, Hc1), 2.05 (t, J=11.9 Hz, 2H, Hb4ax), 1.78 (m, 3H, Hb3eq and Hb2), 1.36 (dq, J=2.5, 11.9 Hz, 2H, Hb3ax).

¹³C NMR (DMSO) δ 162.4 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc3), 148.2 (Cc6), 129.5 (Cc11), 129.1 (Cc10), 124.7 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 119.2 (Cc7), 117.1 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 42.6 (Ca9), 40.6 (Cc2), 35.7 (Cb2), 29.0 (Cb3), 22.4 (Ca10), 11.9 (Ca11).

HRMS-ESI (m/z) calculated for C₂₅H₂₉N₆O [M+H]⁺: 429.2397. found: 429.2404.

Example 8: Compound N

Compound N was synthesized following the same procedure as for Compound G.

4-([1,1′-biphenyl]-4-ylmethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (Compound N)

To a solution of 4-([1,1′-biphenyl]-4-ylmethylamino)-7-((piperidin-4-yl) methoxy)quinazoline (12 mg, 28 μmol), K₂CO₃ (8 mg, 56 μmol) and a catalytic amount of KI in DMF (0.5 mL) was added 26 (14 mg, 56 μmol). The mixture was stirred at 65° C. overnight. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound N as a white powder (5 mg, 84 μmol, 31%).

¹H NMR (500 MHz; CDCl₃) δ 8.67 (s, 1H, Ha1), 8.57 (d, J=5.3 Hz, 1H, Hc5), 8.08 (d, J=8.2 Hz, 1H, Hc8), 7.81 (dd, J=8.2 Hz, 1H, Hc11), 7.70 (ddd, J=1.2, 6.9, 8.2 Hz, 1H, Hc10), 7.46 (ddd, J=1.1, 6.8, 8.2 Hz, 1H, Hc9), 7.66-7.58 (m, 5H, Ha4 and Ha11 and Ha12), 7.56-7.43 (m, 4H, Ha11 and Ha16), 7.38 (m, 1H, Ha17), 7.20 (d, J=2.6 Hz, 1H, Ha7), 7.08 (dd, J=2.6, 9.2 Hz, 1H, Ha5), 6.43 (d, J=5.3 Hz, 1H, Hc4), 6.40 (brs, 1H, HNH), 5.93 (brt, J=5.4 Hz, 1H, HNH), 4.92 (d, J=5.3 Hz, 2H, Ha9), 4.01 (d, J=6.0 Hz, 2H, Hb1), 3.70 (q, J=7.2 Hz, 2H, Ha9), 3.41 (brq, J=4.3 Hz, 2H, Hc2), 3.00 (brd, J=11.5 Hz, 2H, Hb4eq), 2.84 (t, J=5.9 Hz, 2H, Hc1), 2.20 (dt, J=2.0, 12.0 Hz, 2H, Hb4ax), 2.05-1.91 (m, 3H, Hb2 and Hb3eq), 1.52 (dq, J=2.4, 12.5 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 162.4 (Ca6), 159.0 (Ca2), 156.0 (Ca1), 151.7 (Ca8), 150.8 (Cc3), 149.2 (Cc5), 146.1 (Cc6), 140.8 (Ca14), 140.6 (Ca13), 137.3 (Ca10), 129.9 (Cc10), 128.8 (Ca16), 128.5 (Ca11), 128.1 (Cc8), 127.6 (Ca12), 127.4 (Ca17), 125.2 (Cc9), 122.0 (Ca4), 119.7 (Cc11), 118.4 (Cc7), 118.2 (Ca5), 109.0 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.6 (Cb1), 55.7 (Cc1), 52.9 (Cb4), 45.0 (Ca9), 39.1 (Cc2), 35.6 (Cb2), 29.2 (Cb3).

HRMS-ESI(m/z) calculated for C₃₈H₃₉N₆O [M+H]⁺:595.3180. found: 595.3172.

Example 9: Compound Q

Compound Q was synthesized following the same procedure as for Compound G.

6-methyl-N⁴-(2-((7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazolin-4-yl)amino)ethyl)pyrimidine-2,4-diamine (Compound Q)

To a solution of 6-methyl-N4-(2-(7-(piperidin-4-ylmethoxy)quinazolin-4-ylamino)ethyl)pyrimidine-2,4-diamine (95 mg, 0.23 mmol), K₂CO₃ (64 mg, 0.46 mmol) and a catalytic amount of KI in DMF (1.5 mL) was added 26 (113 mg; 46 μmol). The mixture was stirred at 65° C. overnight. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound Q as a white powder (46 mg; 79 μmol; 34%).

¹H NMR (500 MHz, DMSO) δ 8.40 (m, 2H, Hc5 and Ha1), 8.20 (brt, J=8.15 Hz, 1H, HNH), 8.15 (d, J=7.9 Hz, 1H, Hc8), 8.11 (d, J=9.2 Hz, 1H, Ha4), 7.77 (dd, J=1.1, 8.5 Hz, 1H, Hc11), 7.62 (ddd, J=1.1, 7.0, 8.3 Hz, 1H, Hc10), 7.43 (ddd, J=J=1.1, 7.0, 8.3 Hz, 1H, Hc9), 7.11 (dd, J=2.5 Hz, 7.1 Hz, 1H, Ha5), 7.07 (d, J=2.5 Hz, 1H, Ha7), 7.04 (brt, 1H, HNH), 6.48 (d, J=5.2 Hz, 1H, Hc4), 5.84 (brs, 2H, HNH₂), 5.63 (brs, 1H, HNH), 3.98 (d, J=6.0 Hz, 2H, Hb1), 3.65 (brq, J=5.5 Hz, 2H, Ha9), 3.55-3.36 (m, 4H, Ha10 and Hc2), 3.01 (d, J=11.0 Hz, 2H, Hb4eq), 2.64 (t, J=7.0 Hz, Hc1), 2.06 (t, J=11.0 Hz, 2H, Hb4ax), 2.00 (s, 3H, Ha15), 1.86-1.76 (m, 3H, Hb2 and Hb3eq), 1.38 (dq, J=2.8-12.5 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 164.1 (Ca13), 163.3 (Ca14), 162.2 (Ca6), 159.6 (Ca2), 156.0 (Ca1), 151.8 (Ca3), 151.1 (Cc5), 150.3 (Cc7), 148.7 (Cc6), 129.4 (Cc11), 129.1 (Cc10), 124.8 (Ca4), 124.3 (Hc9), 121.9 (Cc8), 119.2 (Cc7), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.8 (Ca12), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 41.2 (a9), 40.6 (Cc2), 39.4 (Ca10), 35.7 (Cb2), 29.0 (Cb3), 23.6 (Ca15).

HRMS-ESI (m/z) calculated for C₃₂H₃₉N₁₀O [M+H]⁺: 579.3303. found: 579.3319.

Example 10: Compound K

1-(methoxymethyl)uracyl (48)

To a solution of uracyl (0.88 g; 7.94 mmol) in 250 mL of dichloromethane was added N,O-bis(trimethylsilyl)acetamide (4.8 mL; 19.4 mmol). The mixture was stirred 1 hour at room temperature. To the reaction mixture was added chloromethyl methyl ether (784 μL; 10.32 mmol) and the mixture was stirred 17 hours at room temperature. The solvent was removed and the residue was purified by silica gel chromatography using the eluent cyclohexane/ethyl acetate (7/3) to give 48 (988 mg; 7.4 mmol; 93%) as a white powder.

¹H NMR (500 MHz; DMSO) δ 11.32 (s, 1H, FINE), 7.70 (d, J=8.0 Hz, 1H, Hc5), 5.61 (d, J=8.0 Hz, 1H, Hc4), 5.02 (s, 2H, Hc7), 3.27 (s, 3H, Hc8).

¹³C NMR (125 MHz, CDCl₃) δ 164.0 (Cc3), 151.5 (Cc6), 145.4 (Cc5), 101.9 (Cc4), 78.0 (Cc7), 56.4 (C8).

HRMS-ESI (m/z) calculated for C₆H₈N₂NaO₃ [M+Na]⁺: 179.0427. Found: 179.0416.

1-(methoxymethyl)-N⁴-(2-(4-(((4-((3-phenylpropyl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)ethyl)cytosine (Compound K)

To a solution of 45 (10 mg; 27 μmol), TEA (30 μL; 0.22 mmol), in DMF (0.2 mL) was added 2-(N-bocamino)ethylbromide (10 mg; 35 μmol). The mixture was stirred at room temperature for 2.5 h. The mixture was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the crude product was immediately solubilized in TFA (0.5 mL). The mixture was stirred at room temperature for 0.5 h. TFA was removed by vacuum. The residue was solubilized in ammonia 7N in methanol and the solvent was removed to afford crude 47 that was used without further purification.

To a solution of triazole (28 mg; 0.40 mmol) and POCl₃ (12 μl; 0.132 mmol) in 0.3 mL of acetonitrile at 0° C. was added TEA 56 μL dropwise. The reaction mixture was stirred at 0° C. for 40 min then 30 min at room temperature. 48 (10 mg; 60 μmol) was added and the mixture was vigorously stirred at room temperature overnight. The solvent was removed and 0.5 mL of a solution of previously prepared 47 was added to the residue. The reaction mixture was stirred 3 h at 35° C. The mixture was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound K (3.5 mg; 60 μmol, 23%) as a white powder.

¹H NMR (500 MHz; CDCl₃) δ 8.57 (s, 1H, Ha1), 7.34-7.28 (m, 3H, Ha4 and Ha13), 7.28-7.20 (m, 4H, Ha15, Ha14 and Hc5), 7.11 (d, J=2.3 Hz, 1H, Ha7), 7.00 (dd, J=2.3, 8.9 Hz, 1H, Ha5), 5.79 (brt, J=4.4 Hz, 1H, HNHc), 5.67 (d, J=7.3 Hz, 1H, Hc4), 5.44 (brt, J=5.5, 1H, HNHa), 5.17 (s, 2H, Hc7), 4.85 (brt, J=5.1 Hz, 1H, HNHc), 3.92 (d, J=5.8 Hz, 2H, Hb1), 3.70 (q, J=7.0 Hz, 2H, Ha9), 3.58 (q, J=4.9 Hz, 2H, Hc2), 3.39 (s, 3H, Hc8), 2.94 (brd, J=10.6 Hz, 2H, Hb4eq), 2.79 (t, J=7.2 Hz, Ha11), 2.55 (t, J=5.7 Hz, 2H, Hc1), 2.11-2.00 (m, 4H, Ha10 and Hb4ax), 1.95-1.79 (m, 3H, Hb2 and Hb3eq), 1.46-1.35 (m, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 163.6 (Cc3), 162.2 (Ca6), 159.0 (Ca2), 157.0 (Cc6), 156.0 (Ca1), 151.6 (Ca8), 142.7 (Cc5), 141.5 (Ca12), 128.6 (Ca13), 128.4 (Ca14), 126.1 (Ca15), 121.8 (Ca4), 117.9 (Ca5), 109.0 (Ca3), 107.8 (Ca7), 95.8 (Cc4), 78.8 (Cc7), 72.7 (Cb1), 56.7 (Cc8), 56.2 (Cc1), 53.0 (Cb4), 41.1 (Ca9), 37.2 (Cc2), 35.6 (Cb2), 33.7 (Ca11), 30.7 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated for C₃₁H₄₀N₇O₃ [M+H]⁺: 558.3187. found: 558.3182.

Example 11: Compound J

4-((2-Hydroxyethyl)amino)pyridine (49)

A mixture of 4-chloropyridine (500 mg; 4.41 mmol) in ethanolamine (2.6 mL; 44 mmol) was stirred at 110° C. for 3 h. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ethyl acetate (0→100% AcOEt) in cyclohexane to afford 49 as a white powder (607 mg; 4.40 mmol; quantitative yield).

¹H NMR (500 MHz, DMSO) δ 8.00 (d, J=6.1 Hz, 1H, Hc5), 6.49 (m, 3H, Hc4 and HNH), 4.77 (brs, 1H, HOH), 3.53 (t, J=6.0 Hz, 2H, Hc1), 3.13 (q, J=5.9 Hz, 2H, Hc2).

¹³C NMR (125 MHz, DMSO) δ : 154.1 (Cc3), 149.7 (Cc5), 107.5 (Cc4), 59.7 (Cc1), 40.6 (Cc2).

HRMS-ESI (m/z) calculated for C₇H₁₀N₂NaO [M+Na]⁺: 161.0685. found: 161.0650.

4-((2-chloroethyl)amino)quinoline chlorhydrate (50)

49 (300 mg; 1.92 mmol) was solubilized in thionyl chloride (2 ml). The mixture was flash boiled and the solvent was removed. Toluene was added to remove the residual thionyl chloride by co-evaporation. The residue was triturated in dichloromethane and the solid was filtrated to afford 50 chlorhydrate as a white solid (360 mg; 1.87 mmol; 97%).

¹H NMR (DMSO) δ 8.22 (brs, 1H, FINE), 8.11 (d, J=6.8 Hz, 2H, Hc5), 6.81 (d, J=6.8 Hz, 2H, Hc4), 3.76 (t, J=6.0 Hz, 2H, Hc1), 3.58 (q, J=5.6 Hz, 2H, Hc2).

¹³C NMR (DMSO) δ : 156.6 (Cc3), 143.9 (Cc5), 107.8 (Cc4), 44.1 (Cc1), 43.5 (Cc2).

HRMS-ESI(m/z) calculated for C₇H₁₀N₂Cl [M+H]⁺: 157.0527. found: 157.0541.

4-(3-phenylpropylamino)-7-((1-(2-(pyridin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (Compound J)

To a solution of 45 (10 mg; 27 μmol), K₂CO₃ (15 mg; 109 μmol) and a catalytic amount of KI in DMF (0.5 mL) was added 50 (13 mg, 68 μmol). The mixture was stirred at 65° C. overnight. The mixture was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound J (9.2 mg, 19 μmol, 69%) as a white powder.

¹H NMR (500 MHz; CDCl₃) δ 8.57 (s, 1H, Ha1), 8.18 (dd, J=1.5, 4.8 Hz, 2H, Hc5), 7.32-7.28 (m, 3H, Ha4 and Ha13), 7.25-7.20 (m, 3H, Ha15 and Ha14), 7.12 (d, J=2.5 Hz, 1H, Ha7), 7.00 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 6.44 (dd, J=1.5, 4.8 Hz, 2H, Hc4), 5.96 (brt, J=5.2, 1H, HNHa), 4.85 (brt, J=5.1 Hz, 1H, HNHc), 3.94 (d, J=6.0 Hz, 2H, Hb1), 3.70 (q, J=6.8 Hz, 2H, Ha9), 3.19 (q, J=5.5 Hz, 2H, Hc2), 2.95 (brd, J=11.4 Hz, 2H, Hb4eq), 2.79 (t, J=7.3 Hz, Ha11), 2.62 (t, J=6.2 Hz, 2H, Hc1), 2.09 (quint, J=6.8 Hz, 2H, Ha10), 2.05 (dt, J=2.1, 9.8 Hz, 2H, Hb4ax), 1.90 (m, 1H, Hb2), 1.87 (d, J=12.2 Hz, 2H, Hb3eq), 1.44 (dq, J=2.9-12.2 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 162.2 (Ca6), 159.0 (Ca2), 155.9 (Ca1), 153.3 (Cc5), 151.5 (Ca8), 150.5 (Cc4), 149.9 (Cc3), 141.5 (Ca12), 128.6 (Ca13), 128.4 (Ca14), 126.1 (Ca15), 121.8 (Ca4), 117.9 (Ca5), 109.0 (Ca3), 107.8 (Ca7), 107.6 (Cc4), 72.7 (Cb1), 56.3 (Cc1), 53.0 (Cb4), 41.1 (Ca9), 38.9 (Cc2), 35.6 (Cb2), 33.6 (Ca11), 30.7 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated for C₃₀H₃₇N₇O [M+H]⁺: 497.3023. found: 497.3025.

Example 12: Compound M

7-O-(piperidin-4-ylmethoxy)quinazolinone (51)

A mixture of 43 (220 mg; 0.46 mmol) in TFA was stirred for 1 h at room temperature. TFA was removed. The residue was diluted with dichloromethane and the organic phase was washed with saturated Na₂CO₃. The solvent was removed and 51 was obtained as pale blue foam (155 mg; 0.43 mmol; 94%).

3-(2-(quinolin-4-ylamino)ethyl)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazolinone (Compound M)

To a solution of 51 (100 mg; 0.39 mmol), K₂CO₃ (160 mg; 1.16 mmol) and a catalytic amount of KI in DMF (5 mL) was added 26 (187 mg; 0.77 mmol). The mixture was stirred at 65° C. overnight and 90° C. for 7 hours. The resulting mixture was filtered and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane to afford Compound M as a white powder (92 mg; 154 μmol; 40%) and Compound L as a white solid (17 mg; 39 μmol; 11%).

¹H NMR (500 MHz; CDCl₃) δ 8.56 (d, J=5.5 Hz, 1H, Hc5), 8.19 (d, J=8.8 Hz, 1H, Ha4), 8.08 (s, 1H, Ha1), 8.03 (d, J=8.5 Hz, 2H, Hc8), 7.78 (d, J=8.5Hzs, 1H, Hc11), 7.65 (ddd, J=1.2, 6.7 Hz, 1H, Hc10), 7.47 (ddd, J=1.2, 6.7 Hz, 1H, Hc9), 7.13-7.06 (m, J=2.4, 8.3 Hz, 1H, Ha5 and Ha7), 6.40 (d, J=5.4 Hz, 1H, Hc4), 7.05 (brs, 1H, HNH), 3.97 (d, J=2.2 Hz, 2H, Hb1), 3.37 (q, J=6.5 Hz, 2H, Hc2), 3.02 (brd, J=11.1 Hz, 2H, Hb4eq), 2.80 (t, J=5.6 Hz, 2H, Hc1), 2.15 (brt, J=11.5 Hz, 2H, Hb4ax), 2.00-1.87 (m, 3H, Hb2 and Hb3eq), 1.54-1.41 (m, 2H, Hb3ax).

¹³C NMR (125 MHz, CDCl₃) δ 164.3 (Ca6), 162.4 (Ca2), 151.2 (Ca8), 150.4 (Ca3), 150.0 (Cc5), 147.1 (Cc6), 144.3 (Ca1), 129.6 (Cc11), 128.8 (Cc10), 127.9 (Ca4), 125.0 (Cc9), 120.0 (Cc8), 118.6 (Cc7), 117.6 (Ca5), 115.9 (Ca3), 109.0 (Ca7), 98.8 (Cc4), 72.8 (Cb1), 58.4 (Cc1), 55.8 (Cb4), 52.9 (Cc2), 39.2 (Cb2), 29.1 (Cb3).

HRMS-ESI (m/z) calculated for C₂₅H₂₇N₅O₂ [M+H]⁺: 430.5216. Found: 430.5223.

¹H NMR (500 MHz; DMSO) δ 8.40 (d, J=5.3 Hz, 2H, Hc5 and Ha14), 8.15 (d, J=8.2 Hz, 1H, Ha4), 8.14 (s, 1H, Ha1), 8.16 (d, J=8.8 Hz, 2H, Hc8 and Ha17), 7.79 (m, 2H, Hc11 and Ha20), 7.61 (m, 2H, Hc10 and Ha19), 7.42 (m, 2H, Hc9 and Ha18), 7.37 (brt, J=6.2 Hz, HNH), 7.14 (dd, J=2.4, 8.3 Hz, 1H, Ha5), 7.07 (d, J=7.07 Hz, 1H, Ha7), 7.05 (brt, J=5.5 Hz, 1H, HNH), 6.66 (d, J=5.3 Hz, 1H, Ha13), 6.47 (d, J=5.3 Hz, 1H, Hc4), 4.22 (t, J=6.0 Hz, 2H, Ha9), 3.99 (d, J=2.0 Hz, 2H, Hb1), 3.69 (q, J=5.8 Hz, 2H, Ha10), 3.41 (q, J=6.3 Hz, 2H, Hc2), 3.00 (brd, J=11.3 Hz, 2H, Hb4eq), 2.68-2.60 (m, 3H, Hc1), 2.07 (t, J=11.0 Hz, 2H, Hb4ax), 1.85-1.72 (m, 3H, Hb2 and Hb3eq), 1.37 (m, 2H, Hb3ax).

¹³C NMR (125 MHz, DMSO) δ 163.8 (Ca6), 160.6 (Ca2), 151.2 (Cc5 and Ca14), 150.7 (Ca8), 150.2 (Cc3), 149.9 (Ca12), 149.0 (Ca1), 148.8 (Cc6), 148.7 (Ca15), 129.6 (Cc11), 129.5 (Ca20), 129.2 (Cc10), 129.1 (Ca19), 128.1 (Ca4), 124.5 (Ca18), 124.3 (Cc9), 121.8 (Cc8), 121.8 (Ca17), 119.3 (Ca16), 119.2 (Cc7), 117.2 (Ca5), 115.4 (Ca3), 109.2 (Ca7), 98.8 (Ca13), 98.7 (Cc4), 72.9 (Cb1), 56.6 (Cc1), 53.4 (Cb4), 44.8 (Ca9), 41.1 (Cc2), 40.6 (Ca10), 35.7 (Cb2), 28.9 (Cb3).

HRMS-ESI (m/z) calculated for C₃₄H₃₈N₅O₂ [M+H]⁺: 600.3080. Found: 600.3076.

Example 13: Compound S

7-(2-(quinolin-4-ylamino)ethoxy)quinazolinone (56)

To a mixture of 25 (143 mg; 760 μmol) in DMF (3 mL) at 0° C. under argon was added sodium hydride (91 mg; 3.81 mmol). The mixture was stirred for 10 min at 0° C. then 42 (250 mg. 1.52 mmol) was added. The mixture was stirred at 110° C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous phase was filtered and the precipitate was dried to afford 56 as a white powder (136 mg; 409 μmol; 54%).

¹H NMR (500 MHz; DMSO) δ 8.43 (d, J=5.3 Hz, 1H, Hc5), 8.24 (dd, J=0.7, 8.5 Hz, 1H, Hc8), 8.06 (s, 1H, Ha1), 8.03 (d, J=8.7 Hz, 1H, Ha4), 7.79 (dd, J=0.7, 8.5 Hz, 1H, Hc11), 7.61 (ddd, J=1.2, 6.7, 8.1 Hz, 1H, Hc10), 7.43 (ddd, J=1.2, 6.7, 8.2 Hz, 1H, Hc9), 7.37 (brt, J=6.0 Hz, 1H, HNHc), 7.15 (d, J=2.6 Hz, 1H, Ha7), 7.13 (dd, J=2.4, 8.9 Hz, 1H, Ha5), 6.61 (d, J=5.4 Hz, 1H, Hc4), 4.42 (t, J=5.5 Hz, 2H, Hc1), 3.75 (q, J=5.5 Hz, 2H, Hc2).

¹³C NMR (125 MHz, DMSO) δ 163.5 (Ca6), 160.7 (Ca2), 151.4 (Ca8), 151.2 (Cc5), 150.2 (Cc3), 148.8 (Cc6), 146.5 (Ca1), 129.5 (Cc11), 129.2 (Cc10), 128.0 (Ca4), 124.3 (Cc9), 122.1 (Cc8), 119.2 (Cc7), 116.9 (Ca5), 116.5 (Ca3), 109.5 (Ca7), 98.9 (Cc4), 66.6 (Cc1), 42.2 (Cc2).

HRMS-ESI (m/z) calculated for C₁₉H₁₇N₄O₂ [M+H]⁺: 333.1346. Found: 333.1350.

4-(3-phenylpropylamino)-7-(2-(quinolin-4-ylamino)ethoxy)quinazoline (Compound S)

To a solution of 56 (50 mg; 13 μmol), TEA (26 mg; 26 μmol) in DMF (1 mL) was added 3-phenylpropylamine (35 mg; 26 μmol). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound S as a white powder (25 mg; 56 μmol; 45%).

¹H NMR (500 MHz; DMSO) δ 8.44 (d, J=5.3 Hz, 1H, Hc5), 8.39 (s, 1H, Ha1), 8.25 (dd, J=0.9, 8.3 Hz, 1H, Hc8), 8.15 (m, 1H, Ha4), 8.10 (brt, J=5.3 Hz, 1H, HNH), 7.79 (dd, J=0.9, 8.5 Hz, 1H, Hell), 7.61 (ddd, J=1.2, 6.9, 8.0 Hz, 1H, Hc10), 7.43 (ddd, J=1.2, 6.9, 8.0 Hz, 1H, Hc9), 7.36 (brt, J=5.2 Hz, 1H, HNHc), 7.32-7.22 (m, 4H, Ha14 and Ha13), 7.17 (m, 1H, Ha15), 7.15-7.10 (m, 2H, Ha7 and Ha5), 6.62 (d, J=5.4 Hz, 1H, Hc4), 4.41 (t, J=5.6 Hz, 2H, Hc1), 3.75 (q, J=5.4 Hz, 2H, Hc2), 3.52 (q, J=5.9 Hz, 2H, Ha9), 2.67 (t, J=7.8 Hz, 2H, Ha11), 1.95 (quint, J=7.8 Hz, 2H, Ha10).

¹³C NMR (125 MHz, DMSO) δ 161.9 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.3 (Cc3), 148.8 (Cc6), 140.9 (Ca12), 129.5 (Cc8), 129.2 (Cc10), 128.8 (Ca13), 128.7 (Ca14), 126.2 (Ca15), 124.3 (Cc9), 122.1 (Ca4), 118.8 (Cc11), 119.2 (Cc7), 117.1 (Ca5), 109.7 (Ca3), 108.0 (Ca7), 98.9 (Cc4), 66.4 (Cc1), 42.3 (Cc2), 40.5 (Ca9), 33.1 (Ca11), 30.8 (Ca10).

HRMS-ESI (m/z) calculated for C₂₈H₂₈N₅O [M+H]⁺: 450.2288. Found: 450.2287.

Example 14: Compound R

3-(3-phenylpropylamino)-7-(O—((N-Boc)piperidin-4-ylmethoxy))quinazoline (58)

To a solution of 43 (150 mg; 42 μmol), K₂CO₃ (115 mg; 84 μmol) in DMF (1.5 mL) was added 1-chloro-3-phenylpropane (129 mg; 84 μmol). The mixture was stirred at 65° C. overnight then was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed to afford 58 as a white powder (190 mg; 40 μmol; 95%).

¹H NMR (500 MHz; DMSO) δ 8.31 (s, 1H, Ha1), 8.05 (d, J=8.4 Hz, 1H, Ha4), 7.31-7.25 (m, 2H Ha13), 7.25-7.20 (m, 2H, Ha14), 7.17 (m, 1H, Ha15), 7.14-7.08 (m, 2H, Ha7 and Ha5), 4.08-3.92 (m, 5H, HNH and Hb1 and Ha9), 2.78 (m, 2H, Hb4ax), 2.74 (t, J=8.5 Hz, 2H, Ha11), 2.07-1.95 (m, 3H, Hb2 and Ha10), 2.10-2.00 (brd, J=11 Hz, 2H, Hb3eq), 1.40 (s, 9H, HBoc), 1.26-1.13 (m, 2H, Hb3ax).

¹³C NMR (125 MHz, DMSO) δ 163.7 (Ca6), 160.2 (Ca2), 154.3 (CBoc), 150.6 (Ca8), 149.0 (Ca1), 1421.4 (CBoc), 128.8 (Ca13), 128.6 (Ca14), 128.1 (Ca4), 126.3 (Ca15), 117.2 (Ca5), 115.4 (Ca3), 109.2 (Ca7), 78.9 (CBoc), 72.6 (Cb1), 46.1 (Ca9), 45.1 (Cb4), 35.6 (Cb2), 32.6 (Ca11), 30.7 (Ca10), 28.6 (Cb3), 28.5 5 (CBoc).

HRMS-ESI (m/z) calculated for C₂₈H₃₅N₃NaO₄ [M+Na]⁺: 500.2520. Found: 500.2516.

3-(3-phenylpropyl)-7-(piperidin-4-ylmethoxy)quinazolinone (59)

A mixture of 58 (190 mg, 40 μmol) in TFA was stirred for 1 h30 at room temperature. TFA was removed. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford 59 as a white powder (124 mg, 33 μmol, 83%).

¹H NMR (500 MHz; CCl₃) δ 8.21 (d, J=8.4 Hz, 1H, Ha4), 7.93 (s, 1H, Ha1), 7.31-7.28 (m, 2H Ha13), 7.26-7.18 (m, 3H, Ha15 and Ha14), 7.08-7.00 (m, 2H, Ha7 and Ha5), 4.03-3.90 (m, 5H, HNH and Hb1 and Ha9), 3.56 (brd, J=9.6 Hz, 2H, Hb4eq), 2.96 (m, 2H, Hb4ax), 2.74 (t, J=7.5 Hz, 2H, Ha11), 2.22-2.10 (m, 3H, Hb2 and Ha10), 2.10-2.00 (m, 2H, Hb3eq), 1.95-1.72 (m, 2H, Hb3ax).

¹³C NMR (125 MHz, CCl₃) δ 163.2 (Ca6), 160.6 (Ca2), 150.2 (Ca8), 147.3 (Ca1), 128.6 (Ca13), 128.4 (Ca4), 128.3 (Ca14), 126.2 (Ca15), 117.2 (Ca5), 115.9 (Ca3), 108.7 (Ca7), 71.6 (Cb1), 46.5 (Ca9), 43.6 (Cb4), 34.1 (Cb2), 32.7 (Ca11), 30.5 (Ca10), 25.6 (Cb3).

HRMS-ESI (m/z) calculated for C₂₃H₂₈N₃O₂ [M+H]⁺: 378.2176. Found: 378.2173.

3-(3-phenylpropyl)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazolinone (Compound R)

To a solution of 59 (124 mg; 0.33 mmol), K₂CO₃ (91 mg; 0.66 mmol) and a catalytic amount of KI in DMF (1.5 mL) was added 26 (80 mg; 0.33 mmol). The mixture was stirred at 65° C. for 24 hours. The solvent was removed and the residue was purified by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound R as a white powder (50 mg; 91 μmol, 28%).

¹H NMR (500 MHz; DMSO) δ 8.40 (d, J=5.5 Hz, 1H, Hc5), 8.35 (s, 1H, Ha1), 8.16 (d, 8.4 Hz, 1H, Hc8), 8.05 (d, J=8.4 Hz, 1H, Ha4), 7.79 (dd, J=0.7, 8.5 Hz, 1H, Hc11), 7.61 (ddd, J=1.2, 6.8, 8.2 Hz, 1H, Hc10), 7.43 (ddd, J=1.2, 6.9, 8.2 Hz, 1H, Hc9), 7.31-7.25 (m, 2H, Ha13), 7.25-7.20 (m, 3H, Ha15 and Ha14), 7.14-7.08 (m, 2H, Ha7 and Ha5), 7.04 (brt, J=4.9 Hz, 1H, HNH), 6.47 (d, J=5.4 Hz, 1H, Hc4), 4.03-3.95 (m, 5H, HNH and Hb1 and Ha9), 3.40 (m, 2H, Hc2), 3.00 (brd, J=11.0 Hz, 2H, Hb4eq), 2.68-2.60 (m, 4H, Ha11 and Hc1), 2.10-1.96 (m, 4H, Hb4ax and Ha10), 1.85-1.72 (m, 3H, Hb2 and Hb3eq), 1.37 (dq, J=2.6, 11.5 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz, DMSO) δ 163.7 (Ca6), 160.2 (Ca2), 151.2 (Cc5), 150.7 (Ca8), 150.2 (Cc3), 149.0 (Ca1), 148.8 (Cc6), 141.5 (Ca12), 129.5 (Cc11), 129.1 (Cc10), 128.7 (Ca13), 128.6 (Ca14), 128.1 (Ca4), 126.3 (Ca15), 124.3 (Cc9), 121.8 (Cc8), 119.2 (Cc7), 117.2 (Ca5), 115.4 (Ca3), 109.2 (Ca7), 98.7 (Cc4), 72.9 (Cb1), 56.6 (Cc1), 53.4 (Cb4), 46.0 (Ca9), 40.5 (Cc2), 35.7 (Cb2), 32.6 (Ca11), 30.7 (Ca10), 29.2 (Cb3).

HRMS-ESI (m/z) calculated for C₃₄H₃₈N₅O₂ [M+H]⁺: 548.3020. Found: 548.3026.

Example 15: Compounds AA to AU

Compounds 60 to 71 were synthesized following the general procedure below from compound 43.

General Procedure for Compounds 60 to 71.

To a solution of triazole (0.93 mmol) and POCl₃ (0.32 mmol) in 0.7 mL of acetonitrile at 0° C. was added TEA (130 μL) dropwise. The reaction mixture was stirred at 0° C. for 40 min then 30 min at room temperature. 43 (0.14 mmol) was added and the mixture was vigorously stirred at room temperature overnight. The reaction was followed by TLC using ethyl acetate as eluent. The mixture was refluxed for 1 h to reach completion. After complete consumption of the starting material, the solvent was removed and the residue was taken off with ethyl acetate and washed with water and brine, and dried over sodium sulfate. The solvent was removed and the residue was solubilized in DMF (0.5 mL). The desired amine (0.23 mmol) and TEA (39 μL; 0.28 mmol) were added and the mixture was stirred for 3 h at room temperature. The mixture was diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ethyl acetate (0 to 100% AcOEt) in cyclohexane to afford 60 to 71.

Amine used Compound obtained

60

61

62

63

64

65

66

67

68

69

70

71

4-(2-(3-chlorophenyl)ethylamino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (60) (70 mg; 0.14 mmol, Quantitative)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.18 (brt, J=5.5 Hz, 1H, HNH), 8.10 (d, J=9.1 Hz, 1H, Ha4), 7.35-7.19 (m, 4H, Ha12, Ha13 et Ha14), 7.11 (dd, J=2.5, 9.1 Hz, 1H, Ha5), 7.06 (d, J=2.5 Hz, 1H, Ha7), 4.03-3.93 (m, 2H, Hb4eq), 3.99 (d, J=6.3 Hz, 2H, Hb1), 3.77-3.71 (m, 2H, Ha9), 2.97 (brt, J=7.0 Hz, 2H, Ha10), 2.85-2.68 (m, 2H, Hb4ax), 2.02-1.93 (m, 1H, Hb2), 1.81-1.74 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.20 (dq, J=4.9, 13.1 Hz, 2H, Hb3ax)

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 142.7 (Ca11), 133.3 (Ca16), 130.5 (Ca15), 129.0 (Ca13), 127.9 (Ca12), 126.5 (Ca14), 124.61 (Ca4), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 42.02 (Ca9), 35.6 (Cb2), 34.5 (Ca10), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 497.2319 [M+H]⁺. found: 497.2342.

4-(2-(2-chlorophenyl)ethylamino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (61) (54 mg, 0.11 mmol, 88%)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.17 (brt, J=5.5 Hz, 1H, HNH), 8.09 (d, J=9.3 Hz, 1H, Ha4), 7.36-7.26 (m, 4H, Ha12, Ha13 et Ha14), 7.11 (dd, J=2.7, 9.12 Hz, 1H, Ha5), 7.06 (d, J=2.3 Hz, 1H, Ha7), 4.04-3.93 (m, 2H, Hb4eq), 3.99 (d, J=6.3 Hz, 2H, Hb1), 3.75-3.69 (m, 2H, Ha9), 2.95 (brt, J=7.3 Hz, 2H, Ha10), 2.83-2.68 (m, 2H, Hb4ax), 2.02-1.92 (m, 1H, Hb2), 1.81-1.73 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.20 (dq, J=3.8, 12.3 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 139.1 (Ca11), 131.14 (Ca16), 131 (Ca15), 128.7 (Ca13), 128.7 (Ca14), 127.7 (Ca12), 124.6 (Ca4), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 43.3 (Cb4), 42.2 (Ca9), 35.6 (Cb2), 34.3 (Ca10), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 497.2319 [M+H]⁺. found: 497.2325.

4-(2-(4-chlorophenyl)ethylamino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (62) (93 mg, 0.14 mmol, Quantitatif)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.21 (brt, J=5.74 Hz, 1H, HNH), 8.10 (d, J=9.20 Hz, 1H, Ha4), 7.47-7.31 (m, 4H, Ha12, Ha13 et Ha14), 7.11 (dd, J=2.47, 8.94 Hz, 1H, Ha5), 7.06 (d, J=2.65, 1H, Ha7), 4.03-3.94 (m, 2H, Hb4eq), 3.98 (d, J=6.41 Hz, 2H, Hb1), 3.80-3.71 (m, 2H, Ha9), 3.09 (brt, J=7.40 Hz, 2H, Ha10), 2.75-2.60 (m, 2H, Hb4ax), 2.02-1.92 (m, 1H, Hb2), 1.81-1.73 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.20 (dq, J=3.94, 12.45 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 138.2 (Ca11), 131.6 (Ca14), 129.6 (Ca12), 127.7 (Ca13), 124.7 (Ca4), 117.3 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 43.1 (Cb4), 42.4 (Ca9), 35.6 (Cb2), 32.8 (Ca10), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 497.2319 [M+H]⁺. found: 497.2318.

4-(2-(4-sulfonamidophenyl)ethylamino)-7-(O—((N-Boc)piperidin-4-ylmethoxy))quinazoline (63) (53 mg, 98 μmol, 70%)

¹H NMR (500 MHz; DMSO) δ 8.42 (s, 1H, Ha1), 8.21 (brt, J=5.8 Hz, 1H, HNH), 8.10 (d, J=9.1 Hz, 1H, Ha4), 7.77-7.73 (m, 2H, Ha13), 7.47-7.43 (m, 2H, Ha12), 7.29 (brs, 2H, Ha15), 7.12 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.07 (d, J=2.5 Hz, 1H, Ha7), 4.02-3.94 (m, 2H, Hb4eq), 3.99 (d, J=6.5 Hz, 2H, Hb1), 3.76 (q, J=6.5 Hz, 2H, Ha9), 3.04 (brt, J=7.4 Hz, 2H, Ha10), 2.84-2.68 (m, 2H, Hb4ax), 2.02-1.92 (m, 1H, Hb2), 1.81-1.74 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.26-1.13 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 144.3 (Ca11), 142.6 (Ca14), 129.6 (Ca12), 126.2 (Ca13), 124.6 (Ca4), 117.3 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 42 (Ca9), 35.6 (Cb2), 34.7 (Ca10), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 542.2437 [M+H]⁺. found: 542.2445.

4-(2-(4-nitrophenyl)ethylamino)-7-(O—((N-Boc)piperidin-4-ylmethoxy))quinazoline (64) (68 mg, 132 μmol, 93%)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.20 (brt, J=5.6 Hz, 1H, HNH), 8.18-8.14 (m, 2H, Ha13), 8.12 (d, J=9.2 Hz, 1H, Ha4), 7.56-7.52 (m, 2H, Ha12), 7.11 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 7.06 (d, J=2.5 Hz, 1H, Ha7), 4.06-3.96 (m, 2H, Hb4eq), 3.98 (d, J=6.3 Hz, 2H, Hb1), 3.74-3.67 (m, 2H, Ha9), 2.94-2.88 (m, 2H, Ha10), 2.88-2.72 (m, 2H, Hb4ax), 2.85 (q, J=6.69 Hz, 1H, Ha15) 2.02-1.94 (m, 1H, Hb2), 1.81-1.75 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.27-1.13 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 146.5 (Ca11), 137.4 (Ca14), 130.6 (Ca12), 124.7 (Ca4), 123.8 (Ca13), 117.2 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 43.2 (Cb4), 42.5 (Ca9), 35.6 (Cb2), 34.7 (Ca10), 28.8 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 508.2559 [M+H]⁺. found: 508.2565.

4-(2-(4-isopropylphenyl)ethylamino)-7-(O—((N-Boc)piperidin-4-ylmethoxy))quinazoline (65) (44 mg, 87 μmol, 62%)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.20 (brt, J=5.6 Hz, 1H, HNH), 8.10 (d, J=9.1 Hz, 1H, Ha4), 7.22-7.14 (m, 4H, Ha12, Ha13), 7.11 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.06 (d, J=2.6 Hz, 1H, Ha7), 4.0-3.96 (m, 2H, Hb4eq), 3.98 (d, J=6.4 Hz, 2H, Hb1), 3.80 (q, J=5.9 Hz, 2H, Ha9), 3.11 (brt, J=7.2 Hz, 2H, Ha10), 2.85-2.67 (m, 2H, Hb4ax), 2.03-1.91 (m, 1H, Hb2), 1.81-1.73 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.26-1.13 (m, 8H, Hb3ax et Ha16).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 154.3 (CBoc), 151.7 (Ca8), 146.5 (Ca14), 137.3 (Ca11), 129.6 (Ca12), 129 (Ca13), 124.7 (Ca4), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 43.2 (Cb4), 42.2 (Ca9), 35.6 (Cb2), 34.8 (Ca10), 33.5 (Ca15), 28.8 (Cb3), 28.6 (CBoc), 24.4 (Ca16).

HRMS-ESI (m/z) calculated: 505.3178 [M+H]⁺. found: 505.3182.

4-(2-(4-methoxyphenyl)ethylamino)-7-(O—((N-Boc)piperidin-4-ylmethoxy))quinazoline (66) (49 mg, 101 μmol, 71%)

¹H NMR (500 MHz; DMSO) δ 8.42 (s, 1H, Ha1), 8.16 (brt, J=5.7 Hz, 1H, HNH), 8.10 (d, J=9.2 Hz, 1H, Ha4), 7.20-7.15 (m, 2H, Ha12), 6.88-6.83 (m, 2H, Ha13), 7.11 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.06 (d, J=2.5 Hz, 1H, Ha7), 4.06-3.94 (m, 2H, Hb4eq), 3.99 (d, J=6.3 Hz, 2H, Hb1), 3.72 (s, 3H, Ha15), 3.71-3.64 (m, 2H, Ha9), 2.88 (brt, J=7.1 Hz, 2H, Ha10), 2.84-2.67 (m, 2H, Hb4ax), 2.04-1.93 (m, 1H, Hb2), 1.83-1.74 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.26-1.12 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 158.1 (Ca14), 156.1 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 144.3 (Ca11), 130.2 (Ca12), 124.6 (Ca4), 117.2 (Ca5), 114.2 (Ca13), 109.6 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 55.4 (Ca15), 43.4 (Cb4), 42.7 (Ca9), 35.6 (Cb2), 34.2 (Ca10), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 493.2814 [M+H]⁺. found: 493.2825.

4-(2-(4-aminophenyl)ethylamino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (67) (67 mg, 0.14 mmol, Quantitative)

¹H NMR (500 MHz; DMSO) δ 8.40 (s, 1H, Ha1), 8.14 (brt, J=5.5 Hz, 1H, HNH), 8.12 (d, J=9.3 Hz, 1H, Ha4), 7.10 (dd, J=2.6, 9.6 Hz, 1H, Ha5), 7.05 (d, J=2.5 Hz, 1H, Ha7), 6.93-6.88 (m, 2H, Ha12), 6.52-6.47 (m, 2H, Ha13) 4.85 (s, 2H, Ha15), 4.06-3.92 (m, 2H, Hb4eq), 3.99 (d, J=6.5 Hz, 2H, Hb1), 3.67-3.57 (m, 2H, Ha9), 2.75 (brt, J=7.5 Hz, 2H, Ha10), 2.84-2.68 (m, 2H, Hb4ax), 2.03-1.92 (m, 1H, Hb2), 1.82-1.73 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.26-1.14 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 147.2 (Ca14), 129.6 (Ca12), 129.3 (Ca11), 114.4 (Ca13), 124.7 (Ca4), 117.1 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 43.1 (Cb4), 42.9 (Ca9), 35.6 (Cb2), 34.4 (Ca10), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 478.2818 [M+H]⁺. found: 478.2831.

4-(2-(quinolinylamino)ethylamino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (68) (52 mg, 98 μmol, 70%)

¹H NMR (500 MHz; DMSO) δ 8.50 (s, 1H, Ha1), 8.42 (d, J=5.3 Hz, 1H, Ha13), 8.16 (dd, J=0.7, 8.2 Hz, 1H, Ha18), 8.10 (d, J=9.2 Hz, 1H, Ha4), 7.79 (dd, J=0.9, 8.5 Hz, 1H, Ha15), 7.61 (ddd, J=0.9, 6.9, 9.3 Hz, 1H, Ha16), 7.45-7.38 (m, 2H, Ha17 and HNH), 7.14 (dd, J=2.5, 9.2 Hz, 1H, Ha5), 7.09 (d, J=2.6 Hz, 1H, Ha7), 6.69 (d, J=5.5 Hz, 1H, Ha12), 4.01-3.94 (m, 4H, Hb1 and Hb4eq), 3.81 (q, J=6.3 Hz, 2H, Ha9), 3.58 (q, J=6.2 Hz, 2H, Ha10), 2.03-1.93 (m, 1H, Hb2), 1.83-1.73 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.26-1.15 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.7 (Ca2), 156.0 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 151.2 (Ca13), 150.3 (Ca11), 148.9 (Ca14), 129.5 (Ca15), 129.1 (Ca16), 124.7 (Ca4), 124.4 (Ca17), 121.9 (Ca18), 119.3 (Ca19), 117.4 (Ca5), 109.6 (Ca3), 108.0 (Ca7), 80.0 (CBoc), 72.4 (Cb1), 42.1 (Ca10), 39.3 (Ca9), 35.6 (Cb2), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 529.2922 [M+H]⁺. found: 529.2928.

4-(2-(naphtylamino)ethylamino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (69) (59 mg, 112 μmol, 79%)

¹H NMR (500 MHz; DMSO) δ 8.51 (s, 1H, Ha1), 8.42 (brt, J=5.1 Hz, 1H, HNH), 8.14 (d, J=9.2 Hz, 1H, Ha19), 8.09 (d, J=7.8 Hz, 1H, Ha4), 7.76 (dd, J=1.8, 6.9 Hz, 1H, Ha15), 7.46-7.35 (m, 2H, Ha17 and Ha18), 7.31 (t, J=7.9 Hz, 1H, Ha13), 7.15 (dd, J=2.5, 9.1 Hz, 1H, Ha5), 7.11 (d, J=8.1 Hz, 1H, Ha14), 7.08 (d, J=2.6 Hz, 1H, Ha7), 6.71 (d, J=7.5 Hz, 1H, Ha12), 6.45 (brt, J=5.1 Hz, HNH), 4.05-3.91 (m, 4H, Hb1 and Hb4eq), 3.85 (q, J=6.3 Hz, 2H, Ha9), 3.51 (brt, J=6.1 Hz, 2H, Ha10), 2.87-2.67 (m, 2H, Hb4ax), 1.98-1.92 (m, 1H, Hb2), 1.81-1.72 (m, 2H, Hb3eq), 1.25-1.15 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.8 (Ca2), 155.9 (Ca1), 154.3 (Ca8), 151.5 (Ca11), 144.3 (Ca11), 134.5 (Ca21), 128.4 (Ca15), 127.6 (Ca13), 126.1 (Ca17), 124.8 (Ca19), 124.7 (Ca4), 124.5 (Ca18), 123.3 (Ca20), 121.8 (Ca4), 117.4 (Ca5), 115.8 (Ca14), 109.5 (Ca3), 107.8 (Ca7), 103.3 (Ca12), 79.0 (CBoc), 72.1 (Cb1), 46.2 (Cb4), 43.2 (Ca10), 39.4 (Ca9), 35.6 (Cb2), 28.7 (Cb3), 28.6 (CBoc).

HRMS-ESI (m/z) calculated: 528.2969 [M+H]⁺. found: 528.3002.

4-(2-(phenylamino)ethylamino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (70) (50 mg, 105 μmol, 75%)

¹H NMR (500 MHz; DMSO) δ 8.42 (s, 1H, Ha1), 8.21 (brt, J=5.6 Hz, 1H, HNH), 8.09 (d, J=9.0 Hz, 1H, Ha4), 7.15 (dd, J=2.7, 9.1 Hz, 1H, Ha5), 7.11-7.05 (m, 3H, Ha7 and Ha13), 6.64 (dd, J=0.9, 8.6 Hz, 2H, Ha12), 6.53 (dt, J=0.9, 7.3 Hz, 2H, Ha14), 5.78 (brt, J=5.9 Hz, HNH), 4.06-3.91 (m, 4H, Hb1 and Hb4eq), 3.67 (q, J=6.5 Hz, 2H, Ha9), 3.30 (brt, J=6.51 Hz, 2H, Ha10), 2.85-2.67 (m, 2H, Hb4ax), 2.03-1.93 (m, 1H, Hb2), 1.82-1.75 (m, 2H, Hb3eq), 1.41 (s, 9H, HBoc), 1.26-1.15 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.6 (Ca2), 156.0 (Ca1), 154.3 (CBoc), 151.8 (Ca8), 149.1 (Ca11), 129.4 (Ca13), 124.7 (Ca4), 117.3 (Ca5), 116.0 (Ca14), 112.4 (Ca12), 109.6 (Ca3), 108.0 (Ca7), 79.0 (CBoc), 72.3 (Cb1), 42.3 (Ca10), 40.2 (Ca9), 35.6 (Cb2), 28.7 (Cb3), 28.56 (CBoc).

HRMS-ESI (m/z) calculated: 478.2813 [M+H]⁺. found: 478.2819.

4-((N-(1-benzylpiperidin-4-yl))amino)-7-(O—((N-Boc) piperidin-4-ylmethoxy))quinazoline (71) (60 mg, 113 μmol, 81%)

¹H NMR (500 MHz; DMSO) δ 8.36 (s, 1H, Ha1), 8.28 (brs, 1H, HNH), 8.21 (d, J=9.2 Hz, 1H, Ha4), 7.73 (d, J=7.6 Hz, 1H, Ha7), 7.37-7.22 (m, 5H, Ha14, Ha15 and Ha16), 7.10 (dd, J=2.6, 9.0 Hz, 1H, Ha5), 7.04 (d, J=2.7 Hz, 1H, Ha7), 4.16-4.10 (m, 1H, Ha9), 4.06-3.86 (m, 3H, Hb1 and Hb4eq), 3.49 (s, 2H, Ha12), 2.86 (brd, J=11.8 Hz, 2H, Hal 1eq), 2.81-2.67 (m, 2H, Hb4ax), 2.06 (dd, J=1.7, 11.8 Hz, 2H, Ha11ax), 2.02-1.92 (m, 1H, Hb2), 1.90 (brd, J=12.4 Hz, 2H, Ha10eq), 1.78 (brd, J=13.4 Hz, 2H, Hb3eq), 1.64 (dd, J=3.6, 12.4 Hz, 2H, Ha10ax), 1.41 (s, 9H, HBoc), 1.19 (dd, J=4.6, 13.4 Hz, 2H, Hb3ax)

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 158.8 (Ca2), 156.0 (Ca1), 154.3 (CBoc), 151.9 (Ca8), 139.2 (Ca13), 129.1 (Ca14), 128.6 (Ca15), 127.3 (Ca15), 124.97 (Ca4), 117.4 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 78.9 (CBoc), 72.3 (Cb1), 62.6 (Ca12), 52.8 (Ca11), 48.2 (Ca9), 35.7 (Cb2), 31.7 (Ca10), 28.7 (Cb3), 28.5 (CBoc).

HRMS-ESI (m/z) calculated: 532.3282 [M+H]⁺. found: 532.3296.

Compounds 72 to 83 were synthesized following the general procedure below from compounds 60 to 71 respectively.

A mixture of the desired compound 60 to 71 in TFA was stirred for 1 h at room temperature. TFA was removed. The residue was diluted with dichloromethane and the organic phase was washed with saturated Na₂CO₃. The solvent was removed and gave respectively compound 72 to 83.

4-(2-(3-chlorophenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (72) (56 mg, 0.14 mmol, Quantitative) from 60 (0.14 mmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.21 (brt, J=5.3 Hz, 1H, HNH), 8.12 (d, J=9.1 Hz, 1H, Ha4), 7.35-7.20 (m, 4H, Ha12, Ha13 et Ha14), 7.11 (dd, J=2.6, 9.0 Hz, 1H, Ha5), 7.07 (d, J=2.54 Hz, 1H, Ha7), 3.96 (d, J=6.4 Hz, 2H, Hb1), 3.77-3.71 (m, 2H, Ha9), 3.11-3.06 (m, 2H, Hb4eq) 2.97 (brt, J=7.1 Hz, 2H, Ha10), 2.68-2.60 (m, 2H, Hb4ax), 2.00-1.89 (m, 1H, Hb2), 1.83-1.74 (m, 2H, Hb3eq), 1.30 (dq, J=2.9, 12.2 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 142.7 (Ca11), 133.3 (Ca16), 130.6 (Ca15), 129.0 (Ca13), 127.9 (Ca12), 126.6 (Ca14) 124.7 (Ca4), 117.2 (Ca5), 109.6 (Ca3), 108 (Ca7), 72.7 (Cb1), 45.1 (Cb4), 42 (Ca9), 34.9 (Cb2), 34.5 (Ca10), 28.5 (cb3).

HRMS-ESI (m/z) calculated: 397.1795 [M+H]⁺. found: 397.1799.

4-(2-(2-chlorophenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (73) (52 mg, 0.13 mmol, 93%) from 61 (0.11 mmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.19 (brt, J=5.6 Hz, 1H, HNH), 8.11 (d, J=9.1 Hz, 1H, Ha4), 7.37-7.22 (m, 4H, Ha12, Ha13 et Ha14), 7.10 (dd, J=2.7, 9.9 Hz, 1H, Ha5), 7.06 (d, J=2.5 Hz, 1H, Ha7), 3.95 (d, J=6.4 Hz, 2H, Hb1), 3.75-3.69 (m, 2H, Ha9), 3.07-3.01 (m, 2H, Hb4eq) 2.95 (brt, J=7.2 Hz, 2H, Ha10), 2.62-2.54 (m, 2H, Hb4ax), 1.97-1.87 (m, 1H, Hb2), 1.82-1.72 (m, 2H, Hb3eq), 1.32-1.20 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 139.1 (Ca11), 131.1 (Ca16), 131 (Ca15), 128.7 (Ca13), 128.7 (Ca14), 126.6 (Ca12) 126.6 (Ca4), 117.2 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 72.9 (Cb1), 45.5 (Cb4), 42.2 (Ca9), 34.6 (Cb2), 34.3 (Ca10), 29.1 (cb3).

HRMS-ESI (m/z) calculated: 397.1795 [M+H]⁺. found: 397.1791.

4-(2-(4-chlorophenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (74) (50 mg, 0.13 mmol, 93%) from 62 (0.14 mmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.23 (m, 1H, HNH), 8.11 (d, J=9.12 Hz, 1H, Ha4), 7.37-7.22 (m, 4H, Ha12, Ha13 et Ha14), 7.13-7.08 (m, 1H, Ha5), 7.08-7.03 (m, 1H, Ha7), 3.95 (d, J=5.95 Hz, 2H, Hb1), 3.75-3.69 (m, 2H, Ha9), 3.07-3.01 (m, 2H, Hb4eq) 2.95 (brt, J=7.20 Hz, 2H, Ha10), 2.62-2.54 (m, 2H, Hb4ax), 1.97-1.87 (m, 1H, Hb2), 1.82-1.72 (m, 2H, Hb3eq), 1.32-1.20 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 139.1 (Ca11), 131.1 (Ca16), 131 (Ca15), 128.7 (Ca13), 128.7 (Ca14), 126.6 (Ca12) 126.6 (Ca4), 117.2 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 72.9 (Cb1), 45.5 (Cb4), 42.2 (Ca9), 34.6 (Cb2), 34.3 (Ca10), 29.1 (cb3)

HRMS-ESI (m/z) calculated: 397.1795 [M+H]⁺. found: 397.1794.

4-(2-(4-sulfonamidophenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (75) (33 mg, 75 μmol, 77%) from 63 (98 μmol)

¹H NMR (500 MHz; DMSO) δ 8.42 (s, 1H, Ha1), 8.21 (brt, J=5.45 Hz, 1H, HNH), 8.10 (d, J=9.11 Hz, 1H, Ha4), 7.77-7.72 (m, 2H, Ha13), 7.47-7.42 (m, 2H, Ha12), 7.37-7.21 (brs, 2H, Ha15), 7.11 (dd, J=2.38, 9.03 Hz, 1H, Ha5), 7.05 (d, J=2.55 Hz, 1H, Ha7), 3.94 (d, J=6.47 Hz, 2H, Hb1), 3.79-3.72 (m, 2H, Ha9), 3.04 (brt, J=7.15 Hz, 2H, Ha10), 2.99-2.92 (m, 2H, Hb4eq), 2.63-2.52 (m, 2H, Hb4ax), 1.93-1.79 (m, 1H, Hb2), 1.76-1.66 (m, 2H, Hb3eq), 1.26-1.12 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 144.3 (Ca11), 142.6 (Ca14), 129.6 (Ca12), 126.2 (Ca13), 124.6 (Ca4), 117.3 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 72.3 (Cb1), 43.2 (Cb4), 42 (Ca9), 35.6 (Cb2), 34.7 (Ca10), 28.7 (Cb3).

HRMS-ESI (m/z) calculated: 397.1795 [M+H]⁺. found: 397.1794.

4-(2-(4-nitrophenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (76) (51 mg, 132 μmol, Quantitative) from 64 (132 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.19 (brt, J=5.40 Hz, 1H, HNH), 8.18-8.14 (m, 2H, Ha13), 8.08 (d, J=9.18 Hz, 1H, Ha4), 7.57-7.52 (m, 2H, Ha12), 7.11 (dd, J=2.56, 9.09 Hz, 1H, Ha5), 7.06 (d, J=2.56 Hz, 1H, Ha7), 3.94 (d, J=6.44 Hz, 2H, Hb1), 3.83-3.76 (m, 2H, Ha9), 3.11 (brt, J=7.20 Hz, 2H, Ha10), 3.03-2.97 (m, 2H, Hb4eq), 2.61-2.53 (m, 2H, Hb4ax), 1.94-1.83 (m, 1H, Hb2), 1.77-1.69 (m, 2H, Hb3eq), 1.26-1.16 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 146.5 (Ca11), 137.4 (Ca14), 130.6 (Ca12), 124.7 (Ca4), 123.8 (Ca13), 117.2 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 72.3 (Cb1), 43.2 (Cb4), 42.5 (Ca9), 35.6 (Cb2), 34.7 (Ca10), 28.8 (Cb3).

HRMS-ESI (m/z) calculated: 408.2035 [M+H]⁺. found: 408.2024.

4-(2-(4-isopropylphenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (77) (34 mg, 80 μmol, 92%) from 65 (87 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.20 (brt, J=5.67 Hz, 1H, HNH), 8.12 (d, J=9.17 Hz, 1H, Ha4), 7.20-7.13 (m, 4H, Ha12, Ha13), 7.11 (dd, J=2.59, 9.03 Hz, 1H, Ha5), 7.06 (d, J=2.73, 1H, Ha7), 3.95 (d, J=6.39 Hz, 2H, Hb1), 3.73-3.66 (m, 2H, Ha9), 3.05-2.97 (m, 2H, Hb4eq), 2.91 (brt, J=7.21 Hz, 2H, Ha10), 2.58-2.53 (m, 2H, Hb4ax), 1.95-1.84 (m, 1H, Hb2), 1.78-1.70 (m, 2H, Hb3eq), 1.29-1.10 (m, 8H, Hb3ax et Ha16).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.7 (Ca8), 146.5 (Ca14), 137.3 (Ca11), 129.6 (Ca12), 129 (Ca13), 124.7 (Ca4), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 72.3 (Cb1), 43.2 (Cb4), 42.2 (Ca9), 35.6 (Cb2), 34.8 (Ca10), 33.5 (Ca15), 28.8 (Cb3), 24.4 (Ca16).

HRMS-ESI (m/z) calculated: 405.2654 [M+H]⁺. found: 405.2659.

4-(2-(4-aminophenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (78) (39.0 mg, 101 μmol, Quantitative) from 66 (101 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.16 (brt, J=5.40 Hz, 1H, HNH), 8.11 (d, J=9.20 Hz, 1H, Ha4), 7.20-7.15 (m, 2H, Ha12), 7.11 (dd, J=2.58, 9.12 Hz, 1H, Ha5), 7.05 (d, J=2.58, 1H, Ha7), 6.88-6.83 (m, 2H, Ha13), 3.94 (d, J=6.38 Hz, 2H, Hb1), 3.72 (s, 3H, Ha15) 3.71-3.65 (m, 2H, Ha9), 3.01-2.92 (m, 2H, Hb4eq), 2.88 (brt, J=7.30 Hz, 2H, Ha10), 2.57-2.52 (m, 2H, Hb4ax), 1.92-1.82 (m, 1H, Hb2), 1.76-1.68 (m, 2H, Hb3eq), 1.26-1.14 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.4 (Ca2), 158.1 (Ca14), 156.1 (Ca1), 151.8 (Ca8), 144.3 (Ca11), 130.2 (Ca12), 124.6 (Ca4), 117.2 (Ca5), 114.2 (Ca13), 109.6 (Ca3), 107.9 (Ca7), 72.3 (Cb1), 55.4 (Ca15), 42.7 (Ca9), 35.6 (Cb2), 34.2 (Ca10), 28.7 (Cb3).

HRMS-ESI (m/z) calculated: 393.2290 [M+H]⁺. found: 393.2297.

4-(2-(4-aminophenyl)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (79) (34 mg, 90 mmol, 64%) from 67 (0.14 mmol)

¹H NMR (500 MHz; DMSO) δ 8.40 (s, 1H, Ha1), 8.13 (brt, J=5.75 Hz, 1H, HNH), 8.11 (d, J=9.58 Hz, 1H, Ha4), 7.11 (dd, J=2.49, 9.10 Hz, 1H, Ha5), 7.04 (d, J=2.63, 1H, Ha7), 6.94-6.86 (m, 2H, Ha12), 6.52-6.46 (m, 2H, Ha13), 4.85 (s, 2H, Ha15), 3.94 (d, J=6.31 Hz, 2H, Hb1), 3.66-3.59 (m, 2H, Ha9), 3.02-2.94 (m, 2H, Hb4eq), 2.76 (brt, J=7.34 Hz, 2H, Ha10), 2.58-2.52 (m, 2H, Hb4ax), 1.94-1.83 (m, 1H, Hb2), 1.76-1.68 (m, 2H, Hb3eq), 1.26-1.15 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 147.2 (Ca14), 129.6 (Ca12), 129.3 (Ca11), 114.4 (Ca13), 124.7 (Ca4), 117.1 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 72.3 (Cb1), 43.1 (Cb4), 42.9 (Ca9), 35.6 (Cb2), 34.4 (Ca10), 28.7 (Cb3).

HRMS-ESI (m/z) calculated: 378.2293 [M+H]⁺. found: 378.2285.

4-(2-(phenylamino)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (80) (3.2 mg, 5.3 μmol, 23%) from 68 (10 mg, 23.3 μmol)

¹H NMR (500 MHz; DMSO) δ 8.49 (s, 1H, Ha1), 8.43 (brt, J=5.7 Hz, 1H, HNH), 8.42 (d, J=5.3 Hz, 1H, Ha13), 8.17 (d, J=6.2 Hz, 1H, Ha18), 8.12 (d, J=9.2 Hz, 1H, Ha4), 7.78 (d, J=8.3 Hz, 1H, Ha15), 7.60 (t, J=7.2 Hz, 1H, Hc10), 7.42 (t, J=7.4 Hz, 1H, Ha17), 7.13 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 7.09 (d, J=2.5 Hz, 1H, Ha7), 6.82 (brt, J=5.1 Hz, 1H, HNH), 6.70 (d, J=5.4 Hz, 1H, Ha12), 3.99 (d, J=5.7 Hz, 2H, Hb1), 3.82 (q, J=6.1 Hz, 2H, Ha9), 3.58 (q, J=6.2 Hz, 2H, Ha10), 3.00 (brd, 2H, Hb4eq), 2.06 (t, J=10.5 Hz, 2H, Hb4ax), 1.865-1.74 (m, 3H, Hb3eq and Hb2), 1.443-1.32 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.3 (Ca6), 159.8 (Ca2), 156.0 (Ca1), 151.8 (Ca8), 151.2 (Ca13), 150.3 (Ca11), 148.7 (Ca14), 129.5 (Ca15), 129.2 (Ca16), 124.7 (Ca4), 124.4 (Ca17), 127.3 (Ca13), 122.0 (Ca18), 121.8 (Ca4), 119.3 (Ca19), 117.5 (Ca5), 109.5 (Ca3), 108.0 (Ca7), 98.5 (Ca12), 72.7 (Cb1), 53.5 (Cb4), 42.1 (Ca10), 39.3 (Ca9), 35.7 (Cb2), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 429.2393 [M+H]⁺. found: 429.2394.

4-(2-(naphtylamino)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (81) (47 mg, 110 μmol, 91%) from 69 (121 μmol)

¹H NMR (500 MHz; DMSO) δ 8.50 (s, 1H, Ha1), 8.38 (brt, J=5.05 Hz, 1H, HNH), 8.12 (d, J=9.16 Hz, 1H, Ha19), 8.11 (d, J=7.6 Hz, 1H, Ha4), 7.76 (dd, J=1.6, 7.1 Hz, 1H, Ha15), 7.47-7.38 (m, 2H, Ha17 and Ha18), 7.31 (t, J=7.9 Hz, 1H, Ha13), 7.15 (dd, J=2.8, 9.1 Hz, 1H, Ha5), 7.11 (d, J=8.4 Hz, 1H, Ha14), 7.08 (d, J=2.5 Hz, 1H, Ha7), 6.71 (d, J=7.6 Hz, 1H, H12), 6.46 (brt, J=5.3 Hz, 1H, HNH), 3.96 (d, J=6.8 Hz, 2H, Hb1), 3.85 (q, J=6.8 Hz, 2H, Ha9), 3.51 (brt, J=6.8 Hz, 2H, Ha10), 3.07-3.00 (m, 2H, Hb4eq), 2.62-2.54 (m, 2H, Hb4ax), 1.97-1.96 (m, 1H, Hb2), 1.81-1.71 (m, 2H, Hb3eq), 1.31-1.20 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.3 (Ca6), 159.8 (Ca2), 156.0 (Ca1), 151.9 (Ca8), 151.8 (Ca11), 144.3 (Ca11), 134.5 (Ca21), 128.4 (Ca15), 127.3 (Ca13), 126.1 (Ca17), 124.7 (Ca19), 124.5 (Ca4), 124.4 (Ca18), 123.3 (Ca20), 121.9 (Ca4), 117.4 (Ca5), 115.8 (Ca14), 109.5 (Ca3), 108.0 (Ca7), 103.2 (Ca12), 72.9 (Cb1), 45.6 (Cb4), 43.2 (Ca10), 39.7 (Ca9), 35.8 (Cb2), 29.2 (Cb3).

HRMS-ESI (m/z) calculated: 428.2445 [M+H]⁺. found: 428.2610.

4-(2-(phenylamino)ethylamino)-7-O-(piperidin-4-ylmethoxy)quinazoline (82) (38 mg, 101 μmol, 96%) from 70 (105 μmol)

¹H NMR (500 MHz; DMSO) δ 8.43 (s, 1H, Ha1), 8.21 (brt, J=5.8 Hz, 1H, HNH), 8.11 (d, J=9.2 Hz, 1H, Ha4), 7.12 (dd, J=2.6, 9.2 Hz, 1H, Ha5), 7.11-7.05 (m, 3H, Ha7 and Ha13), 6.64 (dd, J=0.9, 8.6 Hz, 2H, Ha12), 6.53 (dt, J=0.9, 7.2 Hz, 2H, Ha14), 5.78 (brt, J=6.1 Hz, HNH), 3.96 (d, J=6.4 Hz 2H, Hb1), 3.68 (q, J=6.5 Hz, 2H, Ha9), 3.31 (brt, J=6.5 Hz, 2H, Ha10), 3.08-2.97 (m, 2H, Hb4eq), 2.62-2.547 (m, 2H, Hb4ax), 1.97-1.86 (m, 1H, Hb2), 1.81-1.72 (m, 2H, Hb3eq), 1.32-1.20 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.6 (Ca2), 156.0 (Ca1), 151.8 (Ca8), 149.1 (Ca11), 129.4 (Ca13), 124.7 (Ca4), 117.3 (Ca5), 116.1 (Ca14), 112.4 (Ca12), 109.5 (Ca3), 108.0 (Ca7), 72.9 (Cb1), 45.6 (Cb4), 42.3 (Ca10), 40.1 (Ca9), 35.8 (Cb2), 29.2 (Cb3).

HRMS-ESI (m/z) calculated: 378.2289 [M+H]⁺. found: 378.2280.

4-((N-(1-benzylpiperidin-4-yl))amino)-7-O-(piperidin-4-ylmethoxy)quinazoline (83) (42 mg, 97 μmol, 86%) from 71 (105 μmol)

¹H NMR (500 MHz; DMSO) δ 8.37 (s, 1H, Ha1), 8.28 (brs, 1H, HNH), 8.22 (d, J=9.2 Hz, 1H, Ha4), 7.74 (d, J=7.6 Hz, 1H, Ha7), 7.37-7.24 (m, 4H, Ha14 and Ha15), 7.28-7.23 (m, 1H, Ha16), 7.09 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.04 (d, J=2.6 Hz, 1H, Ha7), 4.20-4.10 (m, 1H, Ha9), 3.95 (d, J=6.4 Hz, 3H, Hb1), 3.49 (s, 2H, Ha12), 3.01 (brd, J=12.2 Hz, 2H, Hb4eq), 2.87 (brd, J=11.7 Hz, 2H, Ha11eq), 2.58 (m, 2H, Hb4ax), 2.06 (dt, J=1.5, 11.7 Hz, 2H, Ha11ax), 1.94-1.85 (m, 3H, Hb2 and Ha10eq), 1.78 (brd, J=10.5 Hz, 2H, Hb3eq), 1.65 (ddd, J=3.7, 11.7 Hz, 2H, Ha10ax), 1.23 (m, 2H, Hb3ax)

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 158.8 (Ca2), 156.0 (Ca1), 151.9 (Ca8), 139.2 (Ca13), 129.1 (Ca14), 128.6 (Ca15), 127.3 (Ca15), 124.9 (Ca4), 117.0 (Ca5), 109.4 (Ca3), 107.9 (Ca7), 72.9 (Cb1), 62.6 (Ca12), 52.8 (Ca11), 48.2 (Ca9), 45.7 (Cb4), 35.9 (Cb2), 31.7 (Ca10), 29.4 (Cb3).

HRMS-ESI (m/z) calculated: 432.2758 [M+H]⁺. found: 432.2753.

Compounds AA to AL were synthesized following the general procedure below from compounds 72 to 83 respectively.

To a solution of 0.1 M of compound 72 to 83 K₂CO₃ (2eq) and a catalytic amount of KI in DMF was added 26 (2eq). The mixture was stirred at 65° C. overnight then was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compounds AA to AL.

4-(2-(3-chlorophenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AA) (5.0 mg, 8.8 μmol, 35%) from 72 (25 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.39 (d, J=5.37 Hz, 1H, Hc5) 8.18 (brt, J=5.35 Hz, 1H, HNH), 8.15 (d, J=8.40 Hz, 1H, Hc8), 8.10 (d, J=9.03 Hz, 1H, Ha4), 7.77 (dd, J=0.89, 8.40 Hz, 1H, Hc11), 7.60 (m, 1H, Hc10), 7.42 (m, 1H, Hc9), 7.36-7.18 (m, 4H, Ha12, Ha13 et Ha14), 7.11 (dd, J=2.6, 9.21 Hz, 1H, Ha5), 7.06 (d, J=2.53, 1H, Ha7), 7.03 (brt, J=5.42 Hz, 1H, HNH), 6.47 (d, J=5.35 Hz, 1H, Hc4), 3.98 (d, J=5.87 Hz, 2H, Hb1), 3.79-3.69 (m, 2H, Ha9), 3.44-3.36 (m, 2H, Hc2), 3.00 (m, 2H, Hb4eq), 2.97 (brt, J=7.13 Hz, 2H, Ha10), 2.63 (t, J=6.69 Hz, 2H, Hc1), 2.06 (m, 2H, Hb4ax), 1.85-1.72 (m, 3H, Hb2 et Hb3eq), 1.45-1.30 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 142.7 (Ca11), 133.3 (Ca16), 130.6 (Ca15), 129.5 (Cc11), 129.1 (Cc10), 129.0 (Ca13), 127.9 (Ca12), 126.5 (Ca14), 124.6 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.6 (Cb4), 42.1 (Ca9), 40.4 (Hc2), 34.5 (Cb2), 34.5 (Ca10), 29 (Cb3)

HRMS-ESI (m/z) calculated: 567.2639 [M+H]⁺. found: 567.2644.

4-(2-(2-chlorophenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AB) (4.0 mg; 7.1 μmol, 29%) from 73 (25 μmol)

¹H NMR (500 MHz; DMSO) δ 8.40 (s, 1H, Ha1), 8.39 (d, J=5.8 Hz, 1H, Hc5) 8.16 (brt, J=5.06 Hz, 1H, HNH), 8.15 (d, J=8.1 Hz, 1H, Hc8), 8.10 (d, J=9.03 Hz, 1H, Ha4), 7.77 (dd, J=0.9, 8.3 Hz, 1H, Hc11), 7.60 (m, 1H, Hc10), 7.42 (m, 1H, Hc9), 7.36-7.24 (m, 4H, Ha12, Ha13 et Ha14), 7.11 (dd, J=2.47, 9.12 Hz, 1H, Ha5), 7.05 (d, J=2.61, 1H, Ha7), 7.03 (brt, J=5.1 Hz, 1H, HNH), 6.47 (d, J=5.3 Hz, 1H, Hc4), 3.98 (d, J=5.7 Hz, 2H, Hb1), 3.77-3.67 (m, 2H, Ha9), 3.44-3.36 (m, 2H, Hc2), 3.04-2.97 (m, 2H, Hb4eq), 2.94 (brt, J=7.1 Hz, 2H, Ha10), 2.63 (t, J=6.8 Hz, 2H, Hc1), 2.06 (m, 2H, Hb4ax), 1.84-1.74 (m, 3H, Hb2 et Hb3eq), 1.44-1.30 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 139.1 (Ca11), 131.14 (Ca16), 131 (Ca15), 129.5 (Cc11), 129.1 (Cc10), 128.7 (Ca13), 128.7 (Ca14), 127.9 (Ca12), 124.6 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 42.2 (Ca9), 40.5 (Hc2), 35.7 (Cb2), 34.53 (Ca10), 29 (Cb3).

HRMS-ESI (m/z) calculated: 567.2639 [M+H]⁺. found: 567.2641.

4-(2-(4-chlorophenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AC) (3.0 mg, 5.3 μmol, 21%) from 74 (25 μmol)

¹H NMR (500 MHz; DMSO) δ 8.40 (s, 1H, Ha1), 8.40 (d, J=5.3 Hz, 1H, Hc5), 8.21 (brt, J=5.6 Hz, 1H, HNH), 8.16 (dd, J=0.9, 8.2 Hz, 1H, Hc8), 8.10 (d, J=9.3 Hz, 1H, Ha4), 7.78 (dd, J=1.1, 8.5 Hz, 1H, Hc11), 7.61 (m, 1H, Hc10), 7.46-7.22 (m, 5H, Hc9, Ha12 and Ha13), 7.11 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.06 (d, J=2.5 Hz, 1H, Ha7), 7.03 (brt, J=5.3 Hz, 1H, HNH), 6.48 (d, J=5.5 Hz, 1H, Hc4), 3.99 (d, J=5.9 Hz, 2H, Hb1), 3.80-3.73 (m, 2H, Ha9), 3.41 (q, J=6.5 Hz, 2H, Hc2), 3.05-2.97 (m, 2H, Hb4eq), 3.09 (brt, J=6.9 Hz, 2H, Ha10), 2.64 (t, J=6.9 Hz, 2H, Hc1), 2.11-2.02 (m, 2H, Hb4ax), 1.85-1.76 (m, 3H, Hb2 et Hb3eq), 1.38 (dq, J=2.5, 12.2 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 137.5 (Ca11), 131.6 (Ca14), 129.6 (Ca12), 129.5 (Cc11), 129.1 (Cc10), 127.7 (Ca13), 124.7 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 46.1 (Ca9), 40.6 (Hc2), 35.7 (Cb2), 32.8 (Ca10), 29 (Cb3).

HRMS-ESI (m/z) calculated: 567.2639 [M+H]⁺. found: 567.2635.

4-(2-(4-sulfonamidophenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AD) (11 mg, 18 μmol, 52%) from 75 (34 μmol)

¹H NMR (500 MHz; DMSO) δ 8.43 (s, 1H, Ha1), 8.40 (d, J=5.3 Hz, 1H, Hc5), 8.21 (brt, J=5.5 Hz, 1H, HNH), 8.16 (dd, J=0.8, 8.8 Hz, 1H, Hc8), 8.11 (d, J=9.1 Hz, 1H, Ha4), 7.78 (dd, J=1.1, 8.4 Hz, 1H, Hell), 7.76-7.72 (m, 2H, Ha13), 7.61 (m, 1H, Hc10), 7.46-7.40 (m, 5H, Hc9, Ha12, Ha15), 7.12 (dd, J=2.6, 9.0 Hz, 1H, Ha5), 7.07 (d, J=2.6 Hz, 1H, Ha7), 7.04 (brt, J=5.5 Hz, 1H, HNH), 6.48 (d, J=5.46 Hz, 1H, Hc4), 3.99 (d, J=5.9 Hz, 2H, Hb1), 3.79-3.73 (m, 2H, Ha9), 3.41 (q, J=6.4 Hz, 2H, Hc2), 3.06-2.97 (m, 4H, Hb4eq, Ha10), 2.64 (t, J=7.2 Hz, 2H, Hc1), 2.10-2.02 (m, 2H, Hb4ax), 1.84-1.77 (m, 3H, Hb2 et Hb3eq), 1.38 (dq, J=2.6, 12.1 Hz, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 144.1 (Ca11), 142.9 (Ca14), 129.5 (Ca12), 129.5 (Cc11), 129.1 (Cc10), 126.1 (Ca13), 124.6 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.3 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 46.1 (Ca9), 40.6 (Cc2), 35.7 (Cb2), 34.7 (Ca10), 29 (Cb3).

HRMS-ESI (m/z) calculated: 612.2756 [M+H]⁺. found: 612.2747.

4-(2-(4-nitrophenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AE) (7 mg, 12 μmol, 33%) from 76 (37 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.40 (d, J=5.3 Hz, 1H, Hc5), 8.21 (brt, J=5.5 Hz, 1H, HNH), 8.18-8.14 (m, 3H, Ha13 et Hc8), 8.09 (d, J=9.2 Hz, 1H, Ha4), 7.78 (dd, J=1.2, 8.4 Hz, 1H, Hell), 7.61 (m, 1H, Hc10), 7.57-7.52 (m, 2H, Ha12), 7.43 (m, 1H, Hc9), 7.12 (dd, J=2.73, 9.25 Hz, 1H, Ha5), 7.06 (d, J=2.64, 1H, Ha7), 7.04 (brt, J=5.54 Hz, 1H, HNH), 6.48 (d, J=5.37 Hz, 1H, Hc4), 3.98 (d, J=5.9 Hz, 2H, Hb1), 3.83-3.77 (m, 2H, Ha9), 3.41 (q, J=8.44 Hz, 2H, Hc2), 3.12 (brt, J=6.9 Hz, 2H, Ha10), 3.04-2.97 (m, 2H, Hb4eq), 2.66-2.61 (m, 2H, Hc1), 2.10-2.02 (m, 2H, Hb4ax), 1.84-1.76 (m, 3H, Hb2 et Hb3eq), 1.44-1.31 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.4 (Ca2), 156 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 146.5 (Ca11), 137.7 (Ca14), 130.5 (Ca12), 129.5 (Cc11), 129.1 (Cc10), 123.8 (Ca13), 124.6 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.4 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 41.9 (Ca9), 40.6 (Cc2), 35.7 (Cb2), 34.8 (Ca10), 29 (Cb3).

HRMS-ESI (m/z) calculated: 578.2879 [M+H]⁺. found: 578.2891.

4-(2-(4-isopropylphenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AF) (1.2 mg, 2.0 μmol, 6%) from 77 (37 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.40 (d, J=5.2 Hz, 1H, Hc5), 8.22 (brt, J=5.9 Hz, 1H, HNH), 8.16 (m, 1H, Hc8), 8.10 (d, J=9.3 Hz, 1H, Ha4), 7.78 (dd, J=1.2, 8.4 Hz, 1H, Hc11), 7.61 (m, 1H, Hc10), 7.45-7.40 (m, 1H, Hc9), 7.20-7.09 (m, 4H, Ha12, Ha13), 7.12 (dd, J=2.56, 9.12 Hz, 1H, Ha5), 7.06 (d, J=2.2 Hz, 1H, Ha7), 7.04 (brt, J=5.3 Hz, 1H, HNH), 6.48 (d, J=5.4 Hz, 1H, Hc4), 3.99 (d, J=5.78 Hz, 2H, Hb1), 3.73-3.68 (m, 2H, Ha9), 3.44-3.38 (m, 2H, Hc2), 3.04-2.98 (m, 2H, Hb4eq), 2.88-2.82 (m, 2H, Ha10), 2.66-2.61 (m, 2H, Hc1), 2.10-2.02 (m, 2H, Hb4ax), 1.83-1.77 (m, 3H, Hb2 et Hb3eq), 1.26-1.16 (m, 8H, Hb3ax et Ha16).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.4 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 146.5 (Ca14), 137.4 (Ca11), 129.5 (Ca12), 129.3 (Ca13), 129.1 (Cc11), 129.1 (Cc10), 124.6 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.2 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 42.5 (Ca9), 40.6 (Cc2), 35.7 (Cb2), 34.7 (Ca10), 29 (Cb3).

HRMS-ESI (m/z) calculated: 575.3498 [M+H]⁺. found: 575.3496.

4-(2-(4-methoxyphenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AG) (15 mg, 27 μmol, 71%) from 78 (38 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (s, 1H, Ha1), 8.40 (d, J=5.37 Hz, 1H, Hc5), 8.18 (brt, J=5.40 Hz, 1H, HNH), 8.16 (m, 1H, Hc8), 8.12 (d, J=9.18 Hz, 1H, Ha4), 7.78 (dd, J=0.9, 8.3 Hz, 1H, Hc11), 7.61 (m, 1H, Hc10), 7.43 (m, 1H, Hc9), 7.20-7.15 (m, 2H, Ha12), 7.12 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.06 (d, J=2.62, 1H, Ha7), 7.04 (brt, J=5.44 Hz, 1H, HNH), 6.88-6.82 (m, 2H, Ha13), 6.48 (d, J=5.4 Hz, 1H, Hc4), 3.98 (d, J=5.9 Hz, 2H, Hb1), 3.72 (s, 3H, Ha15), 3.73-3.64 (m, 2H, Ha9), 3.44-3.38 (m, 2H, Hc2), 3.04-2.96 (m, 2H, Hb4eq), 2.89 (brt, J=7.1 Hz 2H, Ha10), 2.63 (t, J=6.8 Hz, 2H, Hc1), 2.10-2.01 (m, 2H, Hb4ax), 1.84-1.74 (m, 3H, Hb2 et Hb3eq), 1.44-1.31 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.4 (Ca2), 158.1 (Ca14), 156.1 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 131.8 (Ca11), 130.1 (Ca12), 129.5 (Cc11), 129.1 (Cc10), 124.6 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.2 (Ca5), 114.2 (Ca13), 109.6 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 55.4 (Ca15), 53.5 (Cb4), 42.7 (Ca9), 40.6 (Cc2), 35.7 (Cb2), 34.2 (Ca10), 29 (Cb3).

HRMS-ESI (m/z) calculated: 563.3134 [M+H]⁺. found: 563.3145.

4-(2-(4-aminophenyl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AH) (7 mg, 13 μmol, 33%) from 79 (40 μmol)

¹H NMR (500 MHz; DMSO) δ 8.42-8.36 (m, 2H, Hal et Hc5), 8.19-8.13 (m, 2H, HNH et Hc8), 8.12 (d, J=9.08 Hz, 1H, Ha4), 7.78 (dd, J=0.95, 8.45 Hz, 1H, Hc11), 7.61 (m, 1H, Hc10), 7.43 (m, 1H, Hc9), 7.11 (dd, J=2.5, 8.9 Hz, 1H, Ha5), 7.05 (d, J=2.46, 1H, Ha7), 7.04 (brt, J=5.28 Hz, 1H, HNH), 6.93-6.87 (m, 2H, Ha12), 6.52-6.48 (m, 2H, Ha13), 6.48 (d, J=5.4 Hz, 1H, Hc4), 4.86 (s, 2H, Ha15), 3.98 (d, J=5.9 Hz, 2H, Hb1), 3.67-3.58 (m, 2H, Ha9), 3.45-3.38 (m, 2H, Hc2), 3.05-2.97 (m, 2H, Hb4eq), 2.76 (brt, J=7.28 Hz 2H, Ha10), 2.63 (t, J=6.76 Hz, 2H, Hc1), 2.11-2.01 (m, 2H, Hb4ax), 1.84-1.75 (m, 3H, Hb2 et Hb3eq), 1.45-1.31 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.4 (Ca2), 156.2 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc7), 148.7 (Cc6), 147.2 (Ca14), 129.5 (Ca12), 129.5 (Ca11), 129.5 (Cc11), 128.4 (Cc10), 124.7 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 117.2 (Ca5), 114.4 (Ca13), 109.6 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 42.9 (Ca9), 40.6 (Cc2), 35.7 (Cb2), 34.4 (Ca10), 29 (Cb3).

HRMS-ESI (m/z) calculated: 548.3137 [M+H]⁺. found: 548.3142.

4-(2-(quinolin-4-yl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AI) (3.2 mg, 5.3 μmol, 23%) from 80 (23.3 μmol)

¹H NMR (500 MHz; DMSO) δ 8.49 (s, 1H, Ha1), 8.43 (brt, J=5.7 Hz, 1H, HNH), 8.42 (d, J=5.3 Hz, 1H, Ha13), 8.40 (d, J=5.3 Hz, 1H, Hc5), 8.17 (d, J=6.2 Hz, 1H, Ha18), 8.16 (d, J=5.6 Hz, 1H, Hc8), 8.12 (d, J=9.2 Hz, 1H, Ha4), 7.78 (d, J=8.4 Hz, 2H, Hc11 and Ha15), 7.61 (t, J=7.2 Hz, 2H, Hc10 and Ha16), 7.47 (t, J=5.5 Hz, 1H, HNH), 7.43 (t, J=7.6 Hz, 2H, Ha17 and Hc9), 7.14 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 7.09 (d, J=2.5 Hz, 1H, Ha7), 7.06 (brt, J=5.1 Hz, 1H, HNH), 6.70 (d, J=5.4 Hz, 1H, Ha12), 6.48 (d, J=5.4 Hz, 1H, Hc4), 3.99 (d, J=5.7 Hz, 2H, Hb1), 3.82 (q, J=6.1 Hz, 2H, Ha9), 3.58 (q, J=6.2 Hz, 2H, Ha10), 3.41 (m, 2H, Hc2), 3.00 (brd, 2H, Hb4eq), 2.63 (t, J=7.0 Hz, 2H, Hc1), 2.06 (t, J=10.5 Hz, 2H, Hb4ax), 1.865-1.74 (m, 3H, Hb3eq and Hb2), 1.443-1.32 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.3 (Ca6), 159.8 (Ca2), 156.0 (Ca1), 151.8 (Ca8), 151.2 (Cc5 and Ca13), 150.4 (Cc3), 150.3 (Ca11), 148.7 (Ca14), 148.6 (Cc6), 129.5 (Cell and Ca15), 129.2 (Cc10 and Ca16), 124.7 (Ca4), 124.4 (Ca17), 127.3 (Ca13), 122.0 (Cc9 and Ca18), 121.8 (Ca4), 119.3 (Ca19), 119.2 (Cc7), 117.5 (Ca5), 109.5 (Ca3), 108.0 (Ca7), 98.7 (Cc4), 98.6 (Ca12), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 42.1 (Ca10), 40.6 (Hc2), 39.3 (Ca9), 35.7 (Cb2), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 599.3242 [M+H]⁺. found: 599.3241.

4-(2-(naphthalen-1-yl)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AJ) (13 mg, 22 μmol, 63%) from 81 (35 μmol)

¹H NMR (500 MHz; DMSO) δ 8.50 (s, 1H, Ha1), 8.40 (d, J=5.3 Hz, 1H, Hc5), 8.38 (brt, J=5.6 Hz, 1H, HNH), 8.16 (d, J=7.9 Hz, 1H, Hc8), 8.14 (d, J=9.4 Hz, 1H, Ha19), 8.11 (d, J=8.0 Hz, 1H, Ha4), 7.79 (d, J=8.4 Hz, 1H, Hell), 7.75 (dd, J=1.8, 7.5 Hz, 1H, Ha15), 7.61 (ddd, J=0.8, 6.5, 7.7 Hz, 1H, Hc10), 7.45-7.38 (m, 3H, Ha17, Hc9 and Ha18), 7.31 (t, J=7.9 Hz, 1H, Ha13), 7.15 (dd, J=2.7, 9.3 Hz, 1H, Ha5), 7.11 (d, J=7.8 Hz, 1H, Ha14), 7.09 (d, J=2.6 Hz, 1H, Ha7), 7.04 (brt, J=5.2 Hz, 1H, HNH), 6.70 (d, J=7.8 Hz, 1H, Ha12), 6.48-45 (m, 2H, Hc4HNH), 3.99 (d, J=5.9 Hz, 2H, Hb1), 3.86 (q, J=6.0 Hz, 2H, Ha9), 3.51 (q, J=6.0 Hz, 2H, Ha10), 3.41 (q, J=6.3 Hz, 2H, Hc2), 3.05-2.97 (m, 2H, Hb4eq), 2.66-2.60 (m, 2H, Hc1), 2.10-2.02 (t, J=6.9 Hz, 2H, Hb4ax), 1.85-1.75 (m, 3H, Hb3eq and Hb2), 1.43-1.31 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.3 (Ca6), 159.8 (Ca2), 156.0 (Ca1), 151.8 (Ca8), 151.2 (Cc5), 150.2 (Cc3), 148.7 (Cc6), 144.4 (Ca11), 134.5 (Ca21), 129.5 (Cc11), 129.1 (Cc10), 128.4 (Ca15), 127.3 (Ca13), 126.0 (Ca17), 124.7 (Ca19), 124.4 (Ca4), 124.3 (Ca18), 123.3 (Ca20), 121.9 (Ca4), 121.8 (Cc9), 119.2 (Cc7), 117.4 (Ca5), 115.8 (Ca14), 109.5 (Ca3), 108.0 (Ca7), 103.2 (Ca12), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 43.2 (Ca10), 40.6 (Hc2), 39.7 (Ca9), 35.7 (Cb2), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 598.32893 [M+H]⁺. found: 598.3295.

4-(2-(phenylamino)ethylamino)-7-((1-(2-(quinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AK) (11 mg, 20 μmol, 50%) from 82 (40 μmol)

¹H NMR (500 MHz; DMSO) δ 8.42 (s, 1H, Ha1), 8.40 (d, J=5.2 Hz, 1H, Hc5), 8.26 (brt, J=5.5 Hz, 1H, HNH), 8.16 (d, J=7.9 Hz, 1H, Hc8), 8.13 (d, J=9.0 Hz, 1H, Ha4), 7.78 (dd, J=1.0, 8.3 Hz, 1H, Hc11), 7.61 (ddd, J=1.0, 6.8, 8.1 Hz, 1H, Hc10), 7.42 (ddd, j=1.0, 6.9, 7.9 Hz, 1H, Hc9), 7.13 (dd, J=2.5, 9.0 Hz, 1H, Ha5), 7.11-7.02 (m, 3H, Ha7 and Ha13), 6.64 (d, J=7.8 Hz, 2H, Ha12), 6.52 (t, J=7.3 Hz, 2H, Ha14), 6.48 (d, J=7.3 Hz, 1H, Hc4), 5.81 (brt, J=5.8 Hz, 1H, HNH), 3.99 (d, J=5.8 Hz, 2H, Hb1), 3.69 (q, J=6.4 Hz, 2H, Ha9), 3.41 (q, J=6.8 Hz, 2H, Hc2), 3.30 (q, J=6.40 Hz, 2H, Ha10), 3.05-2.97 (m, 2H, Hb4eq), 2.63 (t, J=6.8 Hz, 2H, Hc1), 2.05 (t, J=6.9 Hz, 2H, Hb4ax), 1.86-1.74 (m, 3H, Hb3eq and Hb2), 1.45-1.32 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.6 (Ca2), 156.0 (Ca1), 151.8 (Ca8), 151.1 (Cc5), 150.2 (Cc3), 149.1 (Ca11), 148.7 (Cc6), 129.5 (Cc11), 129.4 (Ca13), 129.1 (Cc10), 124.4 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 119.2 (Cc7), 117.3 (Ca5), 116.0 (Ca14), 112.4 (Ca12), 109.6 (Ca3), 107.9 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 42.4 (Ca10), 40.5 (Hc2), 40.2 (Ca9), 35.7 (Cb2), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 548.3133 [M+H]⁺. found: 548.3140.

4-((N-(1-benzylpiperidin-4-yl))amino)-7-((1-(2-(6,7-dimethoxyquinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AL) (10 mg, 17 μmol, 48%) from 83 (34.7 μmol)

¹H NMR (500 MHz; DMSO) δ 8.40 (d, J=5.3 Hz, 1H, Hc5), 8.37 (s, 1H, Ha1), 8.22 (d, J=9.3 Hz, 1H, Ha4), 8.16 (dd, J=0.9, 7.8 Hz, 1H, Hc8), 7.78 (dd, J=1.0, 8.4 Hz, 1H, Hc11), 7.73 (d, J=7.6 Hz, 1H, Ha7), 7.60 (ddd, J=1.3, 7.3, 8.4 Hz, 1H, Hc10), 7.42 (ddd, j=1.3, 7.3, 8.4 Hz, 1H, Hc9), 7.36-7.29 (m, 4H, Ha14 and Ha15), 7.27-7.23 (m, 1H, Ha16), 7.13-7.05 (m, 3H, Ha5, Hc4 and Ha7), 7.10 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.04 (d, J=2.6 Hz, 1H, Ha7), 7.02 (brt, J=5.3 Hz, 1H, HNH), 6.47 (d, J=5.4 Hz, 1H), 4.20-4.12 (m, 1H, Ha9), 3.97 (d, J=5.9 Hz, 3H, Hb1), 3.49 (s, 2H, Ha12), 3.41 (q, J=6.0, 13.0 Hz, 2H, Hc2), 3.01 (brd, J=11.2 Hz, 2H, Ha11eq), 2.87 (brd, J=11.7 Hz, 2H, Hb4eq), 2.64 (m, 2H, Hc1,), 2.06 (m, 4H, Hal lax and Hb4ax), 1.94-1.86 (m, 3H, Ha10eq), 1.86-1.74 (m, 2H, Hb2 and Hb3eq), 1.65 (ddd, J=3.3, 11.9 Hz, 2H, Ha10ax), 1.45-1.31 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 158.8 (Ca2), 156.0 (Ca1), 151.9 (Ca8), 151.1 (Cc5), 150.2 (Cc3), 148.7 (Cc6), 139.2 (Ca13), 129.5 (Cc11), 129.1 (Ca14), 129.1 (Cc10), 128.6 (Ca15), 127.3 (Ca15), 124.9 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 119.2 (Cc7), 117.0 (Ca5), 109.5 (Ca3), 107.8 (Ca7), 98.7 (Cc4), 72.7 (Cb1), 62.6 (Ca12), 56.6 (Cc1), 53.6 (Ca11), 52.8 (Cb4), 48.2 (Ca9), 40.5 (Cc2), 35.7 (Cb2), 31.7 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 602.3602 [M+H]⁺. found: 602.3603.

Compound 84 was synthesized following the same procedure as for Compound 44 from compound 42.

4-((3-phenylpropyl)amino)-7-(O—((N-Boc)pyrrolidin-4-ylmethoxy))quinazoline (84)

¹H NMR (500 MHz; DMSO) δ 8.39 (s, 1H, Ha1), 8.17 (d, J=9.1 Hz, 1H, Ha4), 8.13 (brt, J=5.1 Hz, 1H, HNH), 7.32-7.22 (m, 4H, Ha13 and Ha14), 7.20-7.16 (m, 1H, Ha15), 7.11 (dd, J=2.4, 8.7 Hz, 1H, Ha5), 7.08 (d, J=2.5 Hz, 1H, Ha7), 4.16-4.05 (m, 2H, Hb1), 3.57-3.48 (m, 3H, Ha9 and Hb5), 3.44-3.24 (m, 2H, Hb4), 3.17-3.09 (m, 1H, Hb5), 2.75-2.60 (m, 3H, Ha11 and Hb2), 2.11-2.01 (m, 1H, Hb3), 1.96 (quint, J=7.3 Hz, 2H, Ha10), 1.80-1.69 (m, 1H, Hb3), 1.41 (s, 9H, HBoc).

¹³C NMR (125 MHz; DMSO) δ 162.0 (Ca6), 159.5 (Ca2), 156.0 (Ca1), 154.0 (CBoc), 151.5 (Ca8), 142.2 (Ca12), 128.8 (Ca14), 128.7 (Ca13), 126.2 (Ca15), 124.8 (Ca4), 117.1 (Ca5), 109.6 (Ca3), 107.9 (Ca7), 78.6 and 78.4 (Cb1), 62.9 (CBoc), 49.0 and 48.7 (Cb5), 45.6 and 45.4 (Cb4), 40.5 (Ca9), 38.3 and 37.4 (Cb2), 33.1 (Ca11), 30.8 (Ca10), 28.6 (CBoc), 28.4 and 27.4 (Cb3).

HRMS-ESI (m/z) calculated: 463.2704 [M+H]⁺. found: 463.2659.

4-((3-phenylpropyl)amino)-7-O-(pyrrolidin-3-ylmethoxy)quinazoline (85)

A mixture of 84 (100 mg; 216 μmol) in TFA was stirred for 1 h at room temperature. TFA was removed. The residue was diluted with dichloromethane and the organic phase was washed with saturated Na₂CO₃. The solvent was removed and 85 was obtained as pale blue foam (60 mg; 166 μmol, 76%).

¹H NMR (500 MHz; DMSO) δ 8.38 (s, 1H, Ha1), 8.15 (d, J=9.5 Hz, 1H, Ha4), 8.09 (brt, J=5.7 Hz, 1H, HNH), 7.32-7.22 (m, 4H, Ha13 and Ha14), 7.18 (m, 1H, Ha15), 7.11 (dd, J=2.9, 9.5 Hz, 1H, Ha5) 7.07 (d, J=2.1 Hz, 1H, Ha7), 4.03-3.97 (m, 2H, Hb1), 3.56-3.49 (m, 2H, Ha9), 2.93-2.79 (m, 2H, Hb5 and Hb4), 2.76-2.60 (m, 4H, Hb5, Hb4 and Ha11), 2.49-2.41 (m, 1H, Hb2), 1.94 (quint, J=7.0 Hz, 2H, Ha10), 1.90-1.80 (m, 1H, Hb3), 1.50-1.39 (m, 1H, Hb3).

¹³C NMR (125 MHz; DMSO) δ 162.2 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.7 (Ca8), 142.2 (Ca12), 128.8 (Ca14), 128.7 (Ca13), 126.2 (Ca15), 124.7 (Ca4), 117.2 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 71.2 (Cb1), 50.4 (Cb5), 46.7 (Cb4), 40.5 (Ca9), 38.7 (Cb2), 33.2 (Ca11), 31.7 (Ca10), 29.4 (Cb3).

HRMS-ESI (m/z) calculated: 363.2180 [M+H]⁺. found: 363.2195.

4-((3-phenylpropyl)amino)-7-((1-(2-(quinolin-4-ylamino)ethyl)pyrrolidin-3-yl) methoxy)quinazoline (AM)

To a solution of 85 (15 mg; 41 μmol), K₂CO₃ (11 mg; 80 μmol) and a catalytic amount of KI in DMF (0.5 mL) was added 26 (16 mg; 80 μmol). The mixture was stirred at 65° C. overnight then was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0 to 10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0 to 80% CH₃CN) to afford Compound AM as a white powder (7 mg; 13 μmol; 31%).

¹H NMR (500 MHz; DMSO) δ 8.38 (s, 1H, Ha1), 8.37 (d, J=5.3 Hz, 1H, Hc5), 8.16 (d, J=7.8 Hz, 1H, Hc8), 8.15 (d, J=9.2 Hz, 1H, Ha4), 8.11 (brt, J=5.9 Hz, 1H, HNH), 7.77 (dd, J=1.0, 8.2 Hz, 1H, Hc11), 7.59 (ddd, J=1.0, 6.8, 8.2 Hz, 1H, Hc10), 7.41 (ddd, j=1.0, 6.8, 8.1 Hz, 1H, Hc9), 7.32-7.22 (m, 4H, Ha13 and Ha14), 7.18 (m, 1H, Ha15), 7.13-7.05 (m, 3H, Ha5, Hc4 and Ha7), 6.47 (d, J=5.4 Hz, 1H), 4.06-3.97 (m, 2H, Hb1), 3.46-3.39 (m, 2H, Hc2), 2.93 (q, J=6.1 Hz, 2H, Ha9), 2.82-2.72 (m, 3H, Hc1+Hb5), 2.72-2.57 (m, 6H, Hb4, Ha10, Hb2 and Ha11), 2.53-2.43 (m, 1H, Hb5), 1.99-1.86 (m, 1H, Hb3), 1.31-1.24 (m, 1H, Hb3).

¹³C NMR (125 MHz; DMSO) δ 162.0 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.7 (Ca8), 151.1 (Cc5), 150.2 (Cc3), 148.7 (Cc6), 142.2 (Ca12), 129.5 (Cc11), 129.1 (Cc10), 128.8 (Ca14), 128.7 (Ca13), 126.2 (Ca15), 124.7 (Ca4), 124.3 (Cc9), 121.9 (Cc8), 119.2 (Cc7), 117.1 (Ca5), 109.6 (Ca3), 108.0 (Ca7), 98.67 (Cc4), 71.6 (Cb1), 57.7 (Cc1), 53.8 (Cb4), 41.9 (Cc2), 40.4 (Ca9), 35.9 (Cb2), 33.7 (Ca11), 31.7 (Ca10), 30.8 (Cb3).

HRMS-ESI (m/z) calculated: 533.3024 [M+H]⁺. found: 533.3025.

Compound AN was synthesized following the general procedure above as for Compound G from 45.

To a solution of 45 (80 mg; 212 μmol), K₂CO₃ (59 mg; 424 μmol) and a catalytic amount of KI in DMF (1 mL) was added 26 (115 mg; 424 μmol). The mixture was stirred at 65° C. overnight then was diluted with ethyl acetate. The organic phase was washed 15 with water and brine and dried over sodium sulfate. The solvent was removed. The crude product was used without further purification and was solubilized in TFA. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compound AN as a white powder (23 mg; 45 μmol; 21%).

¹H NMR (500 MHz; DMSO) δ 8.38 (s, 1H, Ha1), 8.15 (d, J=9.1 Hz, 1H, Ha4), 8.09 (brt, J=5.5 Hz, 1H, HNH), 7.32-7.21 (m, 4H, Ha13 and Ha14), 7.17 (t, J=7.0 Hz, 1H, Ha15), 7.11 (dd, J=2.9, 9.2 Hz, 1H, Ha5), 7.05 (d, J=2.4 Hz, 1H, Ha7), 6.45-6.36 (m, 4H, Hc4 and Hc5), 3.97 (d, J=5.9 Hz, 2H, Hb1), 3.53 (q, J=6.2 Hz, 2H, Ha9), 3.00 (t, J=6.6 Hz, 2H, Hc2), 2.97-2.85 (m, 2H, Hb4eq), 2.68 (t, J=8.0 Hz, 2H, Ha11), 2.47 (t, J=7.1 Hz, 2H, Hc1), 2.01-1.90 (m, 2H, Ha10 and Hb4ax), 1.83-1.73 (m, 3H, Hb3eq and Hb2), 1.42-1.29 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.5 (Ca2), 156.0 (Ca1), 151.7 (Ca8), 142.2 (Ca12), 140.7 (Cc3), 139.6 (Cc6), 128.8 (Cca14), 128.7 (Ca13), 126.2 (Ca15), 124.7 (Ca4), 117.2 (Ca5), 115.9 (Cc4), 114.2 (Cc5), 109.5 (Ca3), 107.9 (Ca7), 72.7 (Cb1), 57.8 (Cc1), 53.5 (Cb4), 42.1 (Cc2), 40.5 (Ca9), 35.8 (Cb2), 33.1 (Ca11), 30.8 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 511.3180 [M+H]⁺. found: 511.3180.

Compounds AO to AS were synthesized following the same procedure as for Compound G from 45.

To a solution of 0.1 M of 45, K₂CO₃ (2eq) and a catalytic amount of KI in DMF was added the desired chloro-derivative (2eq). The mixture was stirred at 65° C. overnight then was diluted with ethyl acetate. The organic phase was washed with water and brine and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel flash chromatography using a linear gradient of ammonia 1N in methanol (0→10% MeOH/NH₃) in dichloromethane or by reversed phase HPLC using a linear acetonitrile gradient with 0.01% of TEA (0→80% CH₃CN) to afford Compounds AO to AS.

Chloro-derivative Compound obtained

AO

AP

AQ

AR

AS

4-((3-phenylpropyl)amino)-7-((1-(2-(7-chloroquinolin-4-ylamino)ethyl) piperidin-4-yl)methoxy)quinazoline (AO) (15 mg, 26 μmol, 97%) from 45 (27 μmol)

¹H NMR (500 MHz; DMSO) δ 8.41 (d, J=5.3 Hz, 1H, Hc5), 8.38 (s, 1H, Ha1), 8.23 (d, J=9.1 Hz, 1H, Hc8), 8.15 (d, J=9.2 Hz, 1H, Ha4), 8.09 (brt, J=5.5 Hz, 1H, HNH), 7.79 (d, J=2.3 Hz, 1H, Hc11), 7.46 (dd, j=2.2, 7.3, 8.9 Hz, 1H, Hc9), 7.32-7.15 (m, 5H, Ha13, Ha14 and Ha15), 7.11 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.05 (d, J=2.6 Hz, 1H, Ha7), 6.51 (d, J=5.4 Hz, 1H, Hc4), 3.98 (d, J=5.9 Hz, 2H, Hb1), 3.53 (q, J=6.1 Hz, 2H, Ha9), 3.41 (q, J=6.5 Hz, 2H, Hc2), 3.01 (brd, J=11.2 Hz, 2H, Ha4eq), 2.68 (t, J=7.5 Hz; 2H, Ha11,) 2.62 (t, J=7.1 Hz, 2H, Hc1,), 2.06 (t, J=11.1 Hz, 2H, Hb4ax), 1.95 (q, J=7.5 Hz, Ha10), 1.83-1.73 (m, 3H, Hb3eq and Hb2), 1.43-1.31 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 152.4 (Cc5), 151.8 (Ca8), 150.4 (Cc3), 149.5 (Cc6), 142.2 (Ca12), 133.8 (Cc10), 128.8 (Ca14), 128.7 (Ca13), 128.0 (Cc11), 126.2 (Ca15), 124.7 (Ca4), 124.5 (Cc9), 124.4 (Cc8), 117.9 (Cc7), 117.2 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 99.2 (Cc4), 72.7 (Cb1), 56.6 (Cc1), 53.5 (Cb4), 40.7 (Ca9), 40.5 (Cc2), 35.7 (Cb2), 33.1 (Ca11), 30.8 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 581.2790 [M+H]⁺. found: 581.2791.

4-((3-phenylpropyl)amino)-7-((1-(2-(7-methoxyquinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AP) (43 mg, 75 μmol, 71%) from 45 (106 μmol)

¹H NMR (500 MHz; DMSO) δ 8.38 (s, 1H, Ha1), 8.32 (d, J=5.3 Hz, 1H, Hc5), 8.15 (d, J=9.2 Hz, 1H, Ha4), 8.10 (brt, J=5.4 Hz, 1H, HNH), 8.06 (d, J=9.1 Hz, 1H, Hc8), 7.32-7.22 (m, 4H, Ha13 and Ha14) 7.21-7.15 (m, 2H, Ha15 and Hc11), 7.11 (dd, J=2.4, 9.1 Hz, 1H, Ha5), 7.08-7.03 (m, 2H, Ha7 and Hc9), 6.96 (brt, J=5.2 Hz, 1H, HNH), 6.36 (d, J=5.5 Hz, 1H, Hc4), 3.97 (d, J=5.7 Hz, 2H, Hb1), 3.87 (s, 3H, Hc12), 3.53 (q, J=6.4 Hz, 2H, Ha9), 3.41-3.36 (m, 2H, Hc2), 3.00 (brd, J=10.9 Hz, 2H, Ha4eq), 2.68 (t, J=7.7 Hz; 2H, Ha11) 2.61 (t, J=6.9 Hz, 2H, Hc1), 2.04 (t, J=11.1 Hz, 2H, Hb4ax), 1.95 (quint, J=7.4 Hz, Ha10), 1.85-1.73 (m, 3H, Hb3eq and Hb2), 1.44-1.31 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 160.0 (Cc3), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 151.5 (Cc5), 150.6 (Cc10), 150.3 (Cc6), 142.2 (Ca12), 128.8 (Ca14), 128.7 (Ca13), 126.2 (Ca15), 124.7 (Ca4), 123.3 (Cc8), 117.2 (Ca5), 116.0 (Cc9), 113.7 (Cc7), 109.5 (Ca3), 108.3 (Cc11), 107.9 (Ca7), 97.6 (Cc4), 72.7 (Cb1), 56.7 (Cc1), 55.6 (Cc12), 53.5 (Cb4), 40.6 (Cc2), 40.5 (Ca9), 35.7 (Cb2), 33.1 (Ca11), 30.8 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 577.3286 [M+H]⁺. found: 577.3296.

4-((3-phenylpropyl)amino)-7-((1-(2-(6,7-dimethoxyquinolin-4-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AQ) (9 mg, 15 μmol, 56%) from 45 (27 μmol)

¹H NMR (500 MHz; DMSO) δ 8.37 (s, 1H, Ha1), 8.22 (d, J=5.3 Hz, 1H, Hc5), 8.15 (d, J=9.3 Hz, 1H, Ha4), 8.11 (brt, J=5.4 Hz, 1H, HNH), 7.45 (s, 1H, Hc8), 7.32-7.21 (m, 4H, Ha13 and Ha14), 7.21-7.15 (m, 2H, Ha15 and Hc11), 7.11 (dd, J=2.6, 9.1 Hz, 1H, Ha5), 7.05 (d, J=2.6 Hz, 2H, Ha7), 6.84 (brt, J=5.2 Hz, 1H, HNH), 6.37 (d, J=5.5 Hz, 1H, Hc4), 3.98 (d, J=5.9 Hz, 2H, Hb1), 3.89 (s, 3H, Hc13), 3.87 (s, 3H, Hc12), 3.56-3.49 (m, 2H, Ha9), 3.41-3.36 (m, 2H, Hc2), 3.00 (brd, J=10.8 Hz, 2H, Ha4eq), 2.68 (t, J=7.7 Hz; 2H, Ha11) 2.63 (t, J=6.9 Hz, 2H, Hc1), 2.06 (t, J=10.8 Hz, 2H, Hb4ax), 1.95 (quint, J=7.4 Hz, Ha10), 1.86-1.75 (m, 3H, Hb3eq and Hb2), 1.47-1.32 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.7 (Cc3), 151.5 (Ca8), 149.3 (Cc9), 148.9 (Cc5), 148.0 (Cc10), 145.4 (Cc6), 142.2 (Ca12), 128.8 (Ca14), 128.7 (Ca13), 126.2 (Ca15), 124.7 (Ca4), 117.2 (Ca5), 113.1 (Cc7), 109.5 (Ca3), 108.7 (Cc11), 107.9 (Ca7), 101.1 (Cc8), 97.9 (Cc4), 72.7 (Cb1), 56.9 (Cc1), 56.3 (Cc13), 55.8 (Cc12), 53.6 (Cb4), 40.7 (Cc2), 40.3 (Ca9), 35.7 (Cb2), 33.1 (Ca11), 30.8 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 607.3391 [M+H]⁺. found: 607.3391.

4-((3-phenylpropyl)amino)-7-((1-(2-(methyl(quinolin-4-yl)amino)ethyl)piperidin-4-yl)methoxy)quinazoline (AR) (13 mg, 23 μmol, 85%) from 45 (27 μmol)

¹H NMR (500 MHz; DMSO) δ 8.61 (d, J=5.1 Hz, 1H, Hc5), 8.38 (s, 1H, Ha1), 8.21 (d, J=8.5 Hz, 1H, Hc8), 8.15 (d, J=9.2 Hz, 1H, Ha4), 8.09 (brt, J=5.4 Hz, 1H, HNH), 7.91 (dd, J=0.7, 8.3 Hz, 1H, Hc11), 7.66 (t, J=7.3 Hz, 1H, Hc9), 7.51 (t, J=7.3 Hz, 1H, Hc10), 7.32-7.22 (m, 4H, Ha13 and Ha14), 7.18 (t, J=7.3 Hz, 1H, Ha15), 7.10 (dd, J=2.5, 9.1 Hz, 1H, Ha5), 7.04 (d, J=2.6 Hz, 1H, Ha7), 6.93 (d, J=5.4 Hz, Hl, Hc4), 3.93 (d, J=5.9 Hz, 2H, Hb1), 3.53 (q, J=5.8 Hz, 2H, Ha9), 3.40 (t, J=6.3 Hz, 2H, Hc2), 2.97 (s, 3H, Hc12), 2.85 (brd, J=10.7 Hz, 2H, Ha4eq), 2.68 (t, J=7.7 Hz, 2H, Ha11,) 2.64 (t, J=6.2 Hz, 2H, Hc1,), 2.02-1.88 (m, 4H, Hb4ax and Ha10), 1.79-1.63 (m, 3H, Hb3eq and Hb2), 1.29-1.15 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.5 (Ca2), 157.1 (Cc3), 156.1 (Ca1), 151.8 (Ca8), 150.8 (Cc5), 149.8 (Cc6), 142.2 (Ca12), 129.9 (Cc11), 129.1 (Cc10), 128.8 (Ca14), 128.7 (Ca13), 126.2 (Ca15), 124.9 (Cc9), 124.7 (Ca4), 124.6 (Cc8), 123.1 (Cc7), 117.1 (Ca5), 109.5 (Ca3), 108.8 (Cc4), 107.9 (Ca7), 72.6 (Cb1), 55.9 (Cc1), 54.2 (Cc2), 53.6 (Cb4), 40.5 (Ca9), 40.2 (Cc12), 35.6 (Cb2), 33.1 (Ca11), 30.8 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 561.3337 [M+H]⁺. found: 561.3339.

4-((3-phenylpropyl)amino)-7-((1-(2-(quinolin-6-ylamino)ethyl)piperidin-4-yl)methoxy)quinazoline (AS) (14 mg, 26 μmol, 96%) from 45 (27 μmol)

¹H NMR (500 MHz; DMSO) δ 8.48 (dd, J=1.63, 4.18 Hz, 1H, Hc11), 8.38 (s, 1H, Ha1), 8.15 (d, J=9.2 Hz, 1H, Ha4), 8.09 (brt, J=5.5 Hz, 1H, HNH), 7.99 (dd, J=0.9, 7.4 Hz, 1H, Hc9), 7.70 (d, J=9.1 Hz, 1H, Hc4), 7.32-7.22 (m, 6H, Ha13, Ha14, Hc5 and Hc10), 7.18 (dt, J=1.4, 7.3 Hz, 1H, Ha15), 7.12 (dd, J=2.5, 9.1 Hz, 1H, Ha5), 7.06 (d, J=2.6 Hz, 1H, Ha7), 6.72 (d, J=5.4 Hz, Hl, Hc8), 5.99 (t, J=5.3 Hz, 1H, HNH), 3.98 (d, J=5.9 Hz, 2H, Hb1), 3.53 (q, J=6.0 Hz, 2H, Ha9), 3.24 (q, J=5.9 Hz, 2H, Hc2), 2.99 (brd, J=11.2 Hz, 2H, Ha4eq), 2.68 (t, J=7.7 Hz, 2H, Ha11), 2.59 (t, J=6.7 Hz, 2H, Hc1,), 2.03 (brt, j=10.8 Hz, 2H, Hb4ax), 1.94 (quint, J=7.4 Hz, 2H, Ha10), 1.85-1.75 (m, 3H, Hb3eq and Hb2), 1.45-1.35 (m, 2H, Hb3ax).

¹³C NMR (125 MHz; DMSO) δ 162.1 (Ca6), 159.5 (Ca2), 156.1 (Ca1), 151.8 (Ca8), 174.3 (Cc3), 145.4 (Cc11), 142.7 (Cc6), 142.2 (Ca12), 133.6 (Cc9), 130.5 (Cc7), 129.8 (Cc4), 128.8 (Ca14), 128.7 (Ca13), 126.2 (Ca15), 124.7 (Ca4), 122.1 (Cc5), 121.7 (Cc10), 117.2 (Ca5), 109.5 (Ca3), 107.9 (Ca7), 101.6 (Cc8), 72.7 (Cb1), 57.3 (Cc1), 53.6 (Cb4), 41.1 (Cc2), 40.5 (Ca9), 35.7 (Cb2), 33.1 (Ca11), 30.8 (Ca10), 29.0 (Cb3).

HRMS-ESI (m/z) calculated: 547.3180 [M+H]⁺. found: 547.3182.

II. Biological Tests of the Compounds According to the Invention

DNMT3A Assay.

DNMT3A enzyme inhibition was adapted from the restriction-based fluorescence assay protocol described in Ceccaldi et al. (ChemBioChem 2011, 12, 1337-45). Briefly, a 5′-labelled biotin oligonucleotide is hybridized to its complementary strand labelled with 6-carboxyfluorescein at the 3′-end into a 384 well microplate (black Optiplates; Perkin Elmer) pre-coated with avidin. The duplex contains a unique CpG site overlapping with a restriction site of a methylation sensitive restriction enzyme. The human C-terminal DNMT3A (a.a. 623-908), produced as described in Gros et al. (Nucleic Acids Research 2013 Aug. 25), was added in each well (200 ng/well) and mixed with the chemical compounds at desired concentrations and freshly prepared AdoMet (20 μM final concentration) to start the reaction in a total volume of 50 μL. After 1 hour incubation at 37° C. each well were washed three times with PBS, Tween-20 0.05%, NaCl (500 mM) and three more times with PBST. Specific fluorescent signals were detected with the methylation-sensitive restriction enzyme HpyCH4IV (NEB) as described and measured on a Perkin Elmer Envision detector. The percentage of inhibition is reported. The formula used to calculate the percentage of inhibition is [(X−Y)/X]×100, where X is the signal determined in the absence of the inhibitor and Y is the signal obtained in the presence of the inhibitor. The concentration at which 50% of efficacy of inhibition is observed (EC50) was determined by analysis of a concentration range of the tested compound in triplicates. The non-linear regression fittings with sigmoidal dose-response (variable slope) were performed with GraphPad Prism 4.03 (GraphPad Software).

DNMT1 Assay.

His-DNMT1 (182 kDa, human) was cloned, expressed and purified as described in Halby et al. (ChemBioChem 2012, 13, 157-65). The reaction was performed in a 10 μL total reaction volume in low volume NBS™ 384-well microplates (Corning), containing the tested compound (up to 1% DMSO), 1 μM of a SAM/[methyl-³H] SAM (3 TBq/mmol, PerkinElmer) mix in a ratio of 3-to-1 (isotopic dilution 1*:3), 0.3 μM of biotinylated hemimethylated DNA duplex (5′-GATmCGCmCGATGmCGmCGAATmCGmCGAT mCGATGmCGAT-3′ and BIOT-5′-ATCGCATCGATCGCGATTCGCGCATCGGCG ATC-3′), and 90 nM of DNMT1 in methylation buffer (20 mM HEPES pH 7.2, 1 mM EDTA, 50 mM KCl, 25 μg/mL BSA). The reaction was incubated at 37° C. for 2 hours. 8 μL are then transferred into a streptavidin 96-well scintillant coated Flashplate™ (PerkinElmer) containing 190 μL of 20 μM SAH in 50 mM Tris-HCl pH 7.4. The Flashplate™ was agitated at room temperature for 1 hour, washed three times with 200 μL of 0.05% Tween®-20 in 50 mM Tris-HCl pH 7.4, and read in 200 μL of 50 mM Tris-HCl pH 7.4 on TopCount NXT (PerkinElmer).

The results of these tests obtained with the compounds of the invention are indicated below:

DNMT1 (% of inhibition) DNMT3A (% of inhibition) 100 32 10 32 20 10 EC₅₀ Compound μM μM μM μM μM μM μM A 97 — — 85 76 60 10   B 86 — — — 67 — — E — — — 51 27 — — F 90 — — 87 76 59 10   G 91.2   24.5 — — 97 81 2.4 H 94.9 — — 69 44 28 — I 99.3 — — 68 32 16 — J 33.7 — — 72 65 47 — K — — — 44 40 10 — L 45 — — 26 — 10 — M 100 100  — 91 — 89 1.1 N 69 24 — 83 — 86 1.1 O 98.4 38 — 99 — 80 4.9 P 22 26 — 81 — 43 13.1  Q 99.6 74 — 68 — 61 5.7 R 98.4 45 — 99 — 65 S 90 — — 95 — 52 AA 97 — — 91 — 82 2.7 AB 97 42 — 100  — — — AC 97 75 — 100  — 88 1.9 AD 100 59 — 93 — — — AE 74 54 — 72 — 61 1.1 AF — — — 83 — 53 AG 59 77 — 100  — 82 3.4 AH 97 59 — 96 — 68 — AI 99 99 — 99 — 86 1   AJ 94 94 — 90 — 91 — AK 93 93 —  5 — 76 — AL 81 81 — 93 — 72 8   AM 100 — — 81 — — — AN — — — 65 — — — AO 79 — — 62 — 70 — AP 90 — — 80 — 70 2.6 AQ 100 61 — 95 — 95 1.4 AR — — — 66 — 66 4.7 AS — — — 60 — 60 —

Anti-Proliferative Activity.

On KG-1 and Karpas 299 Cells:

KG-1 and Karpas299 human leukemia cells were obtained from the ATCC (USA) and cultivated in RPMI 1640 medium (with HEPES and Glutamine, BE12-115F, Lonza, France) supplemented with, respectively, 20% and 15% foetal calf serum (Lonza, France), at 37° C. and under 5% CO₂. To measure the anti-proliferative properties of tested molecules, 2×10⁴ cells are seeded at day 0 in a 96 wells plate. The compounds to be tested, stored at −20° C. as 10⁻² M stock solution in 100% DMSO, are freshly diluted on day 1 in RPMI 1640 medium, before adding a dose range of 3.2 nM to 10 μM to the cells. This treatment is repeated on day 2 and 3, and on day 4 cell viability is assessed using the ATPLite kit from Perkin (ATPlite 1 Step Luminescence Assay System, ref 3016739), following the provider instructions. The raw data are analyzed with GraphPad Prism software (v4.03) to generate EC₅₀ values corresponding to the compound concentrations giving 50% reduction in cell viability. The values presented are the mean results of at least two independent experiments. The 95% confidence intervals for these EC₅₀ values are also indicated.

On WM266.4, U87MG and PANC1 Cells:

The antiproliferative activity of compounds was measured in vitro using the ATP quantification method “ATPlite one step assay” (Perkin Elmer ref 6016739) according to the manufacturer conditions.

Briefly, WM266.4 cells (human melanoma cells) (5×104 cells per ml in RPMI1640 medium, 10% FBS, 2 mM glutamine, 50 U/mL penicillin/streptomycin and 1.25 μg/mL fungizone), PANC1 cells (human pancreatic carcinoma cells) (2×104 cells per ml in DMEM medium, 10% FBS, 2 mM glutamine, 50 U/mL penicillin/streptomycin and 1.25 μg/mL fungizone), and U87MG cells (human neuronal gliablastoma-astrocytoma-cells) (3×104 cells per ml in MEM medium, 10% FBS, 2 mM glutamine, 50 U/mL penicillin/streptomycin and 1.25 μg/mL fungizone) were seeded in 96-well plates, incubated for 24 h and treated with 8 increasing concentrations of test compounds diluted in cells respective mediums, or vehicle in triplicate.

Cells were then incubated for 72 h at 37° C. in humidified 5% CO₂ atmosphere.

At the end of the experiment, cell viability was evaluated by determining the level of ATP released by viable cells.

EC₅₀ values were determined with curve fitting analysis method (non linear regression model with a sigmoid dose response, variable Hill slope coefficient) provided by the Prism Software (GraphPad). Results were expressed as average EC₅₀ values (concentration of tested compound that inhibits 50% of the maximum effect for the considered compound).

The results of these tests obtained with the compounds of the invention are indicated below:

EC₅₀ (μM) Compound KG-1 Karpas299 WN226.4 U87MG PANC1 G 0.5 (0.4-0.6) 1.8 (1.4-2.2) 3.9 8.9 1.2. M 1.3 (1.0-1.6) 0.7 (0.5-1.1) N 0.4 (0.3-0.6) 

The invention claimed is:
 1. A compound of the following formula (I-1c) or (I-1d):

or a pharmaceutically acceptable salt or solvate thereof, wherein: n1 and n2 represent, independently of each other, an integer comprised between 0 and 8, Q represents a cycle of the following formula:

wherein: X₁₁ represents CR₄₁, X₁₂ represents CR₄₂, X₁₃ represents N or C—NR_(43a)R_(43b), X₁₄ represents CR₄₄, X₁₅ represents CR₄₅, R_(43a) and R_(43b) each represent, independently of each other, H or (C₁-C₆)alkyl, R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each other, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₁₇R₂₈, and NR₂₉C(O)R₃₀; or aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀; or in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of the following formula:

wherein: X₁₆ represents CR₄₆, X₁₇ represents CR₄₇, X₁₈ represents CR₄₈, X₁₉ represents CR₄₉, and R₄₆, R₄₇, R₄₈ and R₄₉ each represent, independently of one another, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, and NR₂₉C(O)R₃₀; or aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₁, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, and NR₃₉C(O)R₄₀; W represents NR₀, a piperidinediyl, a piperazinediyl or a pyrrolidinediyl, X₁ represents NH, X₂ represents O, R₀ represents H; CHO; CO₂—((C₁-C₆)alkyl); or a (C₁-C₆)alkyl optionally substituted with CHO, CO₂H or CO₂—((C₁-C₆)alkyl), R₁ and R₂ represent, independently of each other, H or a (C₁-C₆)alkyl, R₃ and R₄ represent, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle, with X₅ representing a bond, O or NR₆ and each aryl or heterocycle moiety being optionally substituted, and R₅ and R₆ represent, independently of each other, H or a (C₁-C₆)alkyl.
 2. The compound according to claim 1, wherein it is a compound of the following formula (I-1c):

or a pharmaceutically acceptable salt or solvate thereof.
 3. The compound according to claim 1, wherein n1 and n2 represent, independently of each other, an integer comprised between 1 and
 4. 4. The compound according to claim 1, wherein W represents NR₀,

the nitrogen atom being linked to (CH₂)_(n1).
 5. The compound according to claim 1, wherein R₃ and R₄ represent, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, —((C₁-C₆)alkyl)-X₅-aryl or —((C₁-C₆)alkyl)-X₅-heterocycle, each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; CO₂R₁₅; OC(O)R₁₆; C(O)NR₁₇R₁₈; NR₁₉C(O)R₂₀; S(O)R₅₀; S(O)₂R₅₁; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, CO₂R₂₅, OC(O)R₂₆, C(O)NR₂₇R₂₈, NR₂₉C(O)R₃₀, S(O)R₅₄, S(O)₂R₅₅, and S(O)₂NR₅₆R₅₇; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, CO₂R₃₅, OC(O)R₃₆, C(O)NR₃₇R₃₈, NR₃₉C(O)R₄₀, S(O)R₅₈, S(O)₂R₅₉, and S(O)₂NR₆₀R₆₁, with R₁₁ to R₄₀ and R₅₀ to R₆₁ representing, independently of one another, H or (C₁-C₆)alkyl.
 6. The compound according to claim 5, wherein R₃ and R₄ represent, independently of each other, H, (C₁-C₆)alkyl, aryl, heterocycle, aryl-(C₁-C₆)alkyl, heterocycle-(C₁-C₆)alkyl, —((C₁-C₆)alkyl)-NH-aryl or —((C₁-C₆)alkyl)-NH-heterocycle, each aryl or heterocycle moiety being optionally substituted with one or several groups selected from halogen; oxo (═O); NO₂; OR₁₁; NR₁₂R₁₃; C(O)R₁₄; S(O)₂NR₅₂R₅₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, NR₂₂R₂₃, C(O)R₂₄, and S(O)₂NR₅₆R₅₇; and aryl or aryl-(C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₃₁, NR₃₂R₃₃, C(O)R₃₄, and S(O)₂NR₆₀R₆₁.
 7. A compound selected from the following compounds:

and the pharmaceutically acceptable salts and solvates thereof.
 8. A pharmaceutical composition comprising at least one compound of formula (I-1c) or (I-1d) according to claim 1 and at least one pharmaceutically acceptable excipient.
 9. A pharmaceutical composition comprising: (i) at least one compound of formula (I-1c) or (I-1d) according to claim 1, and (ii) at least one other active ingredient, as a combination product for simultaneous, separate or sequential use.
 10. A method to prepare a compound of formula (I-1c) or (I-1d) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, in which W═NR₀ with R₀ representing a (C₁-C₆)alkyl optionally substituted with CHO, CO₂H or CO₂—((C₁-C₆)alkyl), comprising: (a) reacting a compound of formula (I-1c) or (I-1d) according to claim 1 in which W═NH with: a compound of formula R₀-LG where R₀ represents a (C₁-C₆)alkyl optionally substituted with CHO, CO₂H or CO₂—((C₁-C₆)alkyl) and LG represents a leaving group to give a compound of formula (I-1c) or (I-1d) in which W═NR₀ with R₀ representing a (C₁-C₆)alkyl optionally substituted with CHO, CO₂H or CO₂—((C₁-C₆)alkyl), dimethylformamide (DMF) to give a compound of formula (I-1c) or (I-1d) in which W═NR₀ with R₀═CHO, or a compound of formula R₀-A₁ where R₀ represents CO₂—((C₁-C₆)alkyl) and A₁ represents a (C₁-C₆)alkoxy group or a halogen atom to give a compound of formula (I-1c) or (I-1d) in which W═NR₀ with R₀ representing CO₂—((C₁-C₆)alkyl), and (b) optionally salifying or solvating the compound obtained in step (a) to give a pharmaceutically acceptable salt or solvate of a compound of formula (I-1c) or (I-1d) according to claim 1 in which W═NR₀ with R₀ as defined above.
 11. A method to prepare a compound of formula (I-1c) or (I-1 d) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, in which W represents NR₀,

comprising: (1) reacting a compound of the following formula (II):

in which Q, X₁ and n1 are as defined in claim 1 and W₁ represents LG₁, NHR₈,

with a compound of the following formula (III-1c) or (III-1d):

in which R₃, R₄, R₅, and n2 are as defined in claim 1 and W₂ represents LG₂, NHR₈,

wherein LG₁ and LG₂ represent, independently of each other, a leaving group and R₈ represents R₀ as defined in claim 1 or a N-protecting group, on the condition that: when W₁ represents LG₁, then W₂ represents NHR₈,

 and when W₁ represents NHR₈,

then W₂ represents LG₂, and, when W₁ or W₂ represents NHR₈ with R₈ representing a N-protecting group, deprotecting the nitrogen atom bearing the N-protecting group, to give a compound of formula (I-1c) or (I-1d) as defined in claim 1, and (2) optionally salifying or solvating the compound obtained in step (1) to give a pharmaceutically acceptable salt or solvate of a compound of formula (I-1c) or (I-1d) as defined in claim
 1. 12. A method to prepare a compound of formula (I-1c) or (I-1d) according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, comprising: (A) reacting a compound of the following formula (VII): Q-X₆  (VII) in which Q is as defined in claim 1 and X₆ represents a halogen atom or —X₁—(CH₂)_(n1)—W—(CH₂)_(n2)—X₂H with W, X₁, X₂, n1 and n2 as defined in claim 1, with a compound of the following formula (VIII-1c) or (VIII-1d):

in which R₃, R₄, and R₅ are as defined in claim 1 and X₇ represents a halogen atom or —X₂—(CH₂)_(n2)—W—(CH₂)_(n1)—X₁H with W, X₁, X₂, n1 and n2 as defined in claim 1, on the condition that: when X₆ represents a halogen atom, then X₇ represents —X₂—(CH₂)_(n2)—W—(CH₂)_(n1)—X₁H, and when X₆ represents —X₁—(CH₂)_(n1)—W—(CH₂)_(n2)—X₂H, then X₇ represents a halogen atom, to give a compound of formula (I-1c) or (I-1d) as defined in claim 1, and (B) optionally salifying or solvating the compound obtained in step (A) to give a pharmaceutically acceptable salt or solvate of a compound of formula (I-1c) or (I-1d) as defined in claim
 1. 13. The compound according to claim 1, wherein: R_(43a) and R_(43b) each represent H, R₄₁, R₄₂, R₄₄ and R₄₅ each represent, independently of each other, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, and NR₂₂R₂₃; or aryl optionally substituted with one or several groups selected from halogen, OR₃₁, and NR₃₂R₃₃, or in the case of R₄₄ and R₄₅, R₄₄ and R₄₅ form together a chain of the following formula:

R₄₆, R₄₇, R₄₈ and R₄₉ each represent, independently of one another, hydrogen; halogen; OR₁₁; NR₁₂R₁₃; (C₁-C₆)alkyl optionally substituted with one or several groups selected from halogen, OR₂₁, and NR₂₂R₂₃; or aryl optionally substituted with one or several groups selected from halogen, OR₃₁, and NR₃₂R₃₃.
 14. The compound according to claim 5, wherein the aryl is a phenyl or a naphtyl and the heterocycle is a saturated, unsaturated or aromatic hydrocarbon monocycle or bicycle, each cycle having 5 or 6 members and 1 to 4 carbon atoms having each been replaced with a nitrogen or oxygen atom.
 15. A method for inhibiting DNA methylation comprising the administration to a person in need thereof of an effective dose of a compound according to claim
 1. 16. The method according to claim 15, for inhibiting a DNA methyltransferase (DNMT). 